You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Understanding why excessive symptoms and frequent exacerbations are poorly controlled in patients with severe asthma is a major unmet need. Uncontrolled daily symptoms despite high-dose inhaled (or oral) corticosteroids with or without bronchodilators impose a major burden on the lives of patients, with implications for their work and social and family life, and exacerbations are costly for healthcare systems ([@bib1]--[@bib4]).

Symptoms are difficult to measure because they are highly subjective and can be confounded by anxiety or depression. Cough is a common troublesome asthma symptom that can be experimentally evoked by inhaled cough stimuli ([@bib5]) and objectively quantified by 24-hour cough monitoring ([@bib6]). Capsaicin is a commonly used cough challenge agent that is known to activate TRPV1 (transient receptor potential vanilloid-1), which is found predominantly on unmyelinated c-fibers ([@bib7]). Hence, capsaicin cough challenge can be used as an experimental model to investigate functional nerve responses in patients with asthma.

In a study presented in this issue of the *Journal*, Kanemitsu and colleagues (pp. [1068--1077](10.1164/rccm.201911-2263OC)) investigated the associations of capsaicin cough reflex sensitivity, as measured by the concentration of capsaicin causing two or five coughs (C2/C5), with clinical, physiological, and inflammatory features in patients with severe asthma ([@bib8]). The clinical features were divided into two groups based on a combination of the degree of asthma control as measured by Asthma Control Questionnaire (\>1.5) or Asthma Control Test (\<20), exacerbation frequency (≥2 burst of oral steroids for ≥3 d), and hospitalizations (≥1). In a univariate analysis, heightened cough reflex sensitivity (lower C2/C5) and higher absolute serum neutrophil counts (\>5,000/μl) were associated with poor asthma control, frequent exacerbations, and hospitalizations. However, this was confined mainly to nonatopic patients, where the mechanisms of clinical features remain poorly understood. In a multivariate analysis, heightened C5 increased the odds of poor asthma control (odds ratio \[OR\], 4.83), exacerbations (OR, 2.83), and a trend toward hospitalization (OR, 3.43). When compared with other variables, poor asthma control (Asthma Control Test \< 20) was most strongly influenced by heightened cough reflex sensitivity (C5), followed by FEV~1~ \< 80% predicted, with some borderline significant contributions from being a nonatopic, ex-smoker with higher serum neutrophil counts. In contrast, greater exacerbation frequency (≥2) was most strongly influenced by FEV~1~ \< 80% predicted, followed by heightened cough reflex sensitivity and a borderline significant contribution from being female (OR, 3.34). Finally, hospitalizations were influenced most strongly by patients who were ex-smokers, with a FEV~1~ \< 80% predicted, raising the possibility these patients had chronic airflow limitation.

This is the first study to show that heightened cough reflex sensitivity in patients with severe asthma is linked to clinical features such as poor asthma control and higher rates of exacerbations. This suggests that neuronal dysfunction is an important phenotype of severe asthma, and that novel treatments targeting excessive coughing may need to target peripheral airway nerves and/or the central pathways in the brainstem and higher cortical centers involved in the cough reflex.

Investigators have been reluctant to perform capsaicin cough challenges in subjects with severe asthma because of the risk of bronchoconstriction in those with persistent airway inflammation and lower FEV~1~. Only in the last few years have data emerged showing that capsaicin cough challenge does not cause bronchoconstriction in the vast majority of individuals with mild/moderate asthma ([@bib9]), has no effect on airway hyperresponsiveness ([@bib10]), is safe after induction of bronchoconstriction ([@bib10]), and can be performed safely in patients with severe asthma ([@bib11]). The only caveats are that FEV~1~ should be checked before and after a challenge, and inhaled β~2~-agonists should be available in case there is a significant fall in FEV~1~ associated with worsening symptoms. In this study, the investigators routinely gave salbutamol to every patient at the end of the capsaicin challenge without measuring FEV~1~, but, reassuringly, none of the patients required emergency treatment during the challenge itself.

As the authors recognize, the results should be interpreted with caution. This was a prospective observational study, and the authors did not assess airway inflammation in patients with severe asthma by measuring sputum differential cell counts. In addition, atopy was defined by negative specific serum IgE. The authors describe non--type 2 disease as the absence of atopy (i.e., non--IgE mediated) accompanied by low blood eosinophil counts, and this definition is imprecise. Patients were on moderate/high doses of inhaled corticosteroids, and it is not surprising that blood eosinophils were low and blood neutrophils were in the normal range. Previous observational data from subjects with mild/moderate asthma showed no relationship between capsaicin cough responses or 24-hour cough counts and blood ([@bib9]) or sputum ([@bib12]) eosinophil counts at baseline. However, after allergen challenge, an increase in sputum eosinophils after 24 hours was associated with increased capsaicin-evoked cough responses ([@bib13]). This implies that inducing eosinophilic airway inflammation sensitizes the airway nerves. This notion was corroborated by a recent study that showed increased colocalization of eosinophils with airway nerves in patients with asthma ([@bib14]).

Mucus or inflammatory cell debris in the airways as a plausible cause of coughing was not addressed. This was recently highlighted by elegant imaging studies that demonstrated ventilation heterogeneity ([@bib15]) and reductions in total airway counts in patients with severe asthma ([@bib16]). How these luminal and structural changes impact nerve structure and function remain unknown.

This study, as well as future mechanistic or interventional studies of cough in asthma, could be strengthened by measuring spontaneous objective 24-hour coughs. The relationship between cough reflex sensitivity and spontaneous hourly cough rates is weak ([@bib17]), although a distinction has to be made between cough reflex sensitivity (lower C2/C5) and cough hyperresponsiveness. The latter can only be demonstrated by performing a full capsaicin dose--response analysis to measure the maximum number of evoked coughs (Emax) ([@bib9]). Whether inhibiting the cough reflex has any effects on reducing spontaneous objective cough rates is of questionable clinical utility. Two double-blind, randomized controlled trials of TRPV1 antagonists in patients with chronic refractory cough failed to show any impact on hourly cough rates, although one study using a highly potent TRPV1 antagonist demonstrated a significant reduction in capsaicin Emax ([@bib18], [@bib19]). However, these trials did not include patients with moderate or severe asthma; hence, TRPV1 antagonists could still play a role in asthma.

The concept of neurophenotypes in airway disease has previously been demonstrated in a study that used different cough challenge stimuli in airway diseases ([@bib20]). The current study by Kanemitsu and colleagues further suggests that neuronal dysfunction is an important phenotype that influences asthma control and exacerbations. Broader questions remain as to whether the mechanism of TRPV1 hypersensitivity is peripherally and/or centrally driven, how type 2 and non--type 2 inflammatory cells and mucus affect airway nerves, and, importantly, whether any antitussives currently in development (e.g., P2X3 and NK-1 antagonists) or currently available biologics targeting IL-5 and IL-4/13 will improve cough in moderate-to-severe uncontrolled asthma. Future studies will be required to answer these important questions.

Originally Published in Press as DOI: [10.1164/rccm.202002-0228ED](http://dx.doi.org/10.1164/rccm.202002-0228ED) on February 12, 2020

[**[Author disclosures](http://www.atsjournals.org/doi/suppl/10.1164/rccm.202002-0228ED/suppl_file/disclosures.pdf)**]{.ul} are available with the text of this article at [www.atsjournals.org](http://www.atsjournals.org).