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]


Introduction {#sec1_1}
============

Alagille syndrome (arteriohepatic dysplasia) is a rare autosomal dominant disorder, caused by mutations in the *JAG1* gene located on the short arm of chromosome 20 \[[@B1]\]. Classic features include intrahepatic bile-duct hypoplasia causing neonatal cholestatic jaundice, cardiovascular defects, skeletal abnormalities and a characteristic facial appearance \[[@B2]\]. Additional common findings include renal abnormalities, growth retardation and mental retardation \[[@B3]\]. Alagille syndrome is also associated with ocular abnormalities, most commonly with posterior embryotoxon, which is present in 95% of cases and is considered a major feature of this disorder \[[@B4]\]. Other ocular abnormalities include retinal pigmentary changes, optic disc abnormalities, lens opacities, iris abnormalities and a slightly reduced corneal diameter without significant refractive errors \[[@B4], [@B5], [@B6]\]. Patients with Alagille syndrome have a relatively good prognosis, and are typically managed with pruritus-relieving medication and nutritional supplementation of the fat-soluble vitamins (A, D, E and K) \[[@B2], [@B7], [@B8]\].

We report a patient with Alagille syndrome, with significant bilateral keratopathy secondary to reduced vitamin A levels that had occurred despite nutritional supplementation.

Case Report {#sec1_2}
===========

A 3-year-old boy was examined at our institution due to severe bilateral ocular-surface disease, more severe in the right eye. His medical history included neonatal cholestatic jaundice, which prompted us to make a thorough systemic evaluation. Liver biopsy revealed paucity of the intrahepatic bile ducts. Cardiac echography revealed a left-to-right shunt through an atrial septal defect and mild stenosis of the pulmonary arteries. Vertebral structure was normal on X-ray. The patient was first examined at our clinic at the age of 9 months, and a prominent posterior embryotoxon was noted bilaterally (fig. [1](#F1){ref-type="fig"}). The combination of typical facial characteristics including a prominent forehead, bulbous nose and pointed chin together with systemic and ocular findings led to a clinical diagnosis of Alagille syndrome. His parents were reluctant to have genetic testing performed. During infancy, the main complaint was his failure to thrive, and a percutaneous endoscopic gastrostomy tube was inserted for added caloric supplementation along with the fat-soluble vitamins. The patient suffered from a significant developmental delay (e.g. he started walking only at the age of 2.5 years) and severe growth retardation under full caloric and pancreatic-enzyme supplementation (at the age of 3.5 years, he weighed 7.2 kg, which is below the 3rd percentile). He received chronic daily treatment with ursodeoxycholic acid and supplementation with the fat-soluble vitamins (AquADEKs, 1 ml until the age of 1 year, and then 2 ml; 1 ml contains vitamin A as 87% β-carotene and 13% palmitate, 5,751 IU which is 383% of the daily value for infants).

Several months prior to examination at our clinic, he started complaining of severe bilateral ocular irritation. Because of constant eye-rubbing, it was assumed that he suffered from vernal keratoconjunctivitis, and he was treated with topical antihistamines. After failing to improve with this treatment, he was referred for our examination. At the initial evaluation, a central corneal ulcer was noted in the right eye, with marked opacity and central thinning of the cornea. The cornea in the left eye displayed mild opacities and diffuse superficial punctate keratitis. The fundus could not be seen in the right eye, but in the left eye, mild tilting and optic-disc pallor were noted as well as a few retinal pigmentary changes. A culture taken from the corneal ulcer in the right eye was positive for *Staphylococcus mitis*. The patient was treated with intensive topical cefamezine, garamycin and lubrication, and experienced a gradual improvement. Three weeks after his initial presentation to our clinic, the corneal infiltrate resolved, but a marked thinning remained. He underwent amniotic membrane transplantation with lower punctual occlusion (fig. [2](#F2){ref-type="fig"}). Due to the clinical findings and his systemic condition, a suspicion of vitamin A deficiency was raised. This was confirmed by serum analysis of vitamin A, which measured 2 μg/dl; this is significantly lower than the normal range of 30--120 μg/dl. There were no Bitot\'s spots in either eye. It should be noted that, due to the patient\'s significant developmental delay, visual acuity could not be measured and he was unable to articulate any complaint regarding reduced vision or nyctalopia. The vitamin A supplementation was further increased and it resulted in a gradual improvement of the degree of ocular discomfort within the following months. The irritation had resolved, the patient was no longer rubbing his eyes, and the right cornea was adequately covered by conjunctival epithelium.

Discussion {#sec1_3}
==========

Vitamin A is an essential fat-soluble vitamin that has many systemic as well as ocular effects. In the eye, it is essential for the normal turnover of epithelial cells and mucin production and for the production of visual pigments in the photoreceptor cells \[[@B9]\]. Vitamin A deficiency is the leading cause of preventable childhood blindness worldwide \[[@B9]\]; however, this condition is rare in the Western world, where its occurrence is usually caused by lipid malabsorption, chronic liver disease or unusual dietary restrictions \[[@B10], [@B11], [@B12], [@B13]\]. Ocular disease due to vitamin A deficiency is termed xerophthalmia, which typically develops in a sequential order \[[@B9]\]. Night blindness is usually the earliest manifestation, followed by ocular-surface changes which range from mild conjunctival and corneal drying (xerosis) to corneal ulceration and melting (keratomalacia) and eventually to pigmentary retinopathy \[[@B9]\]. An association between systemic vitamin A deficiency and increased intracranial pressure has also been described \[[@B14]\]. The World Health Organization (WHO) has published a classification of ocular changes secondary to vitamin A deficiency \[[@B15]\]. Our patient was compatible with the WHO classification class X~3~A in the right eye, presenting with corneal ulceration and keratomalacia involving one third or less of the cornea, and class X~2~ in the left eye, which only had corneal xerosis. Although the child had previously been treated with vitamin A supplementation, the level of this vitamin in his body was markedly reduced. He also had significant growth retardation, and it is possible that the combination of his body\'s high demand for growth, chronic cholestasis and low storage capability due to his liver disease resulted in his vitamin A deficiency, despite dietary supplementation. Improvement occurred only when the vitamin A dosage was further increased.

The pigmentary retinopathy typical for Alagille syndrome has been presumed to relate to a deficiency of vitamins A and E \[[@B5], [@B16]\]; however, recent reports have identified normal serum levels of these vitamins in patients harboring retinal changes \[[@B3], [@B4]\]. None of the publications previously reporting on the ocular complications of Alagille syndrome have described keratomalacia from vitamin A deficiency.

In conclusion, this case is unique since it is the first to describe xerophthalmia and keratomalacia in a patient with Alagille syndrome. It is also remarkable for the documented vitamin A deficiency and associated xerophthalmia despite dietary supplementation. This case also illustrates the potential hazards of vitamin A deficiency on the eyes, and should raise the awareness of corneal specialists and general ophthalmologists to this entity, which has become rare in the developed world.

![At the age of 9 months, a prominent posterior embryotoxon was visible in the corneal periphery (shown in the right eye, present bilaterally).](cop-0004-0311-g01){#F1}

![Bilateral manifestations of xerophthalmia. **a** Right eye -- the cornea is opaque and covered by an amniotic membrane. **b** Left eye -- conjunctival irritation and corneal opacification.](cop-0004-0311-g02){#F2}