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]


Findings
========

Introduction
------------

The prevalence of pediatric cases within the general uveitis population is estimated to range from 5% to 13.8% \[[@B1]-[@B3]\]. The treatment of uveitis in children is challenging due to the lack of verbalization of symptoms, difficult examination, and suboptimal compliance to the recommended treatment \[[@B4]\]. Corticosteroids remain the mainstay of treatment but are associated with unique complications in children especially when used systemically, such as growth retardation \[[@B5]-[@B7]\]. Intravitreal triamcinolone has been used to treat uveitic macular edema but is associated with a significant risk of increased intraocular pressure and cataract \[[@B8],[@B9]\]. A novel dexamethasone intravitreal implant (Ozurdex^®^, Allergan Inc., Irvine, CA, USA) has been shown to significantly improve intraocular inflammation, visual acuity, and central macular thickness in adults with non-infectious intermediate or posterior uveitis \[[@B10]\]. Recently, control of inflammation and resolution of cystoid macular edema (CME) was achieved with dexamethasone implant in 13 out of 14 eyes of patients with pediatric uveitis \[[@B11]\]. We present a rare case of a child followed for bilateral recalcitrant uveitic macular edema despite systemic immunosuppression who responded to dexamethasone intravitreal implants.

Case report
-----------

An 11-year-old boy of Nigerian descent was followed for bilateral granulomatous idiopathic panuveitis and orbital inflammation for 14 months (Figure [1](#F1){ref-type="fig"}). His past medical history was significant for hemoglobin SC disease and G6PD deficiency. At the onset of the disease, a rheumatologic workup with anti-nuclear antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, and HLA-B27 testing was negative. Serology for Lyme disease, toxoplasmosis, toxacariasis, cat scratch disease, human immunodeficiency virus, leptospirosis, coccidioidomycosis, and histoplasmosis was negative. Syphilis was also ruled out by a negative RPR and TP-PA. His serum calcium level was slightly elevated, but the angiotensin converting enzyme level and chest X-ray were normal. A biopsy of an enlarged right lacrimal gland biopsy was performed. Pathologic analysis was inconclusive and showed a non-specific non-granulomatous lymphocytic inflammation. A Mantoux test result showed 4 mm of induration and was considered positive as the patient came from an endemic area and was at that time treated with high-dose intravenous corticosteroids for his ocular inflammation. The patient was treated with anti-tuberculous triple-drug therapy for 2 months and then with rifampin for 4 months. Triple-drug therapy was discontinued as the patient was diagnosed with latent tuberculosis by infectious disease specialists. Indeed, he showed a positive response to corticosteroids, and aqueous and vitreous fluid cultures were negative for mycobacteria.

![**Color fundus photographs and fluorescein angiogram at presentation.** (top right and top left) Both eyes showed optic nerve edema, dilated veins, and macular edema. (bottom right and bottom left) Late-phase fluorescein angiogram showed leakage of the optic nerve head that was more evident in the left eye, as well as patchy hyperfluorescence of the macula and petaloid leakage at the fovea in both eyes.](1869-5760-3-61-1){#F1}

The patient had undergone a diagnostic vitrectomy with intravitreal injection of triamcinolone acetonide in the left eye 3 months after presentation for worsening of macular edema despite treatment with subcutaneous methotrexate for 6 weeks. The vitreous biopsy yielded negative cultures for bacteria, mycobacteria, fungus, and parasites. The central foveal thickness dramatically decreased from 1,002 μm preoperatively to 238 μm with complete resolution of the uveitic macular edema at 1 month after surgery.

Over the last 3 months, his best-corrected visual acuity had decreased from 20/40 in the right eye (OD) and 20/30 in the left eye (OS) to 20/200 in both eyes (OU). Slit lamp examination showed mutton-fat keratic precipitates, 4+ anterior chamber cells, and 3+ flare. Both eyes showed 4+ vitreous cells. Dilated fundus examination showed bilateral disc edema, dilated and sheathed veins, and macular edema. Optical coherence tomography (OCT) showed CME and subretinal fluid with a central foveal thickness of 592 μm OD and 435 μm OS (Figure [2](#F2){ref-type="fig"}). His treatment regimen included prednisolone drops 1% every hour, dexamethasone ointment 0.1% and homatropine drops 2% bid OU, subcutaneous methotrexate 20 mg weekly, and oral folic acid 2 mg daily.

![**Optical coherence tomography before bilateral injections of dexamethasone intravitreal implant.** Optical coherence tomography showed marked cystoid macular edema in the right eye. (top) The left eye showed subretinal fluid and minimal cystoid macular edema (bottom). The central retinal thickness was 592 μm in the right eye and 435 μm in the left eye.](1869-5760-3-61-2){#F2}

Given the refractory nature of the uveitic macular edema despite therapeutic levels of methotrexate, the prior positive response to intravitreal steroid and the vitrectomized status of the left eye, off-label bilateral injections of dexamethasone intravitreal implant were performed under general anesthesia. On post-operative day 1, the methotrexate was substituted for oral mycophenolate mofetil 500 mg daily, which was gradually increased to 750 mg bid. His visual acuity improved to 20/80 OD and 20/50 OS 3 weeks after the injections. Three months post-operatively, his visual acuity was 20/30 OD and 20/40 OS. He showed fine keratic precipitates, 2+ anterior chamber cells, and 1+ vitreous cells OU. The intraocular pressures were in the normal range and the both eyes showed posterior subcapsular cataracts. Both optic nerves showed reduced edema. The OCT showed absence of CME and subretinal fluid in both eyes (Figure [3](#F3){ref-type="fig"}).

![**Optical coherence tomography 3 months after bilateral injections of dexamethasone intravitreal implant.** Both eyes showed absence of cystoid macular edema and subretinal fluid (OD, top; OS, bottom). The central retinal thickness was 338 μm in the right eye and 261 μm in the left eye.](1869-5760-3-61-3){#F3}

The patient did not experience significant uveitic macular edema recurrence requiring local treatment over the next 2 years. Further systemic therapy with infliximab, which was added 11 months after the Ozurdex injections, has achieved excellent control of his uveitis.

Discussion
----------

CME is a common complication of pediatric uveitis with a prevalence of approximately 30% at 3 years from initial presentation \[[@B3],[@B6]\]. In a large case series of 527 pediatric uveitis patients, CME was second only to hypotony as the uveitic complication with the most significant visual impact \[[@B6]\]. Our patient demonstrated macular edema that was refractory to topical steroids and immunosuppression with methotrexate but that was exquisitely responsive to vitrectomy and intravitreal triamcinolone acetonide in one eye.

When he experienced a second flare-up of his uveitic macular edema, the newly available Ozurdex^®^ implant was considered because of its duration of action and its stability in vitrectomized eyes. The half-life of intravitreal triamcinolone acetonide is shorter in a vitrectomized eye, its concentration decreasing 1.5 times more rapidly than in a non-vitrectomized eye \[[@B12]\]. On the other hand, Ozurdex^®^ exhibits a vitreous concentration of dexamethasone that is sustained over time to a similar extent in vitrectomized and non-vitrectomized eyes \[[@B13]\]. Moreover, pharmacokinetic and pharmacodynamic data suggest that when injected into the posterior segment, the implant releases dexamethasone into the vitreoretinal tissues for up to 6 months \[[@B14]\]. Three months after the injections, our patient experienced a significant visual acuity improvement and a normalization of his OCT in both eyes. He did not show increased intraocular pressure but posterior subcapsular cataracts started to develop. The methotrexate treatment was replaced by mycophenolate mofetil around the same time that the implants were injected and it may have assisted in the macular edema control. Mycophenolate mofetil takes several weeks to have an effect and probably did not play a significant role in the initial control of the macular edema. However, it possibly helped to keep the macula dry after the effect of the implants wore off.

This case did not only represent a therapeutic challenge, but also a diagnostic one. Tuberculosis was first considered as the etiology of our patient's uveitis but that hypothesis was later abandoned. Although a strong suspicion for sarcoid-associated uveitis and orbital disease was raised, this diagnosis could not be confirmed despite an extensive work-up including a biopsy of an enlarged lacrimal gland. The etiology was therefore labeled as idiopathic.

In a previous report of the use of the Ozurdex^®^ intravitreal implant for the treatment of uveitis in children, 31% of treated eyes that showed an initial response relapsed within 6 months of their injection, at a median time of 4 months \[[@B11]\]. This finding stresses the importance of concomitant systemic immunosuppressive therapy to achieve long-term control of ocular inflammation. Lowder et al. showed that dexamethasone intravitreal implant was effective in controlling ocular inflammation and had an advantageous safety profile, with less than 10% of treated eyes having an intraocular pressure of 25 mmHg or greater and no significant increased risk of cataract \[[@B10]\]. Nevertheless, they did not study the safety profile of repeated injections. We believe that Ozurdex^®^ has a role in the treatment of pediatric uveitis or its complications, such as macular edema, which are not well controlled with systemic therapy or when compliance with medication may be a problem.

Consent
-------

Written informed consent was obtained from the patient's guardian/parent/next of kin for the publication of this report and any accompanying images.

Abbreviations
=============

CME: Cystoid macular edema; OD: Right eye; OS: Left eye; OU: Both eyes; OCT: Optical coherence tomography.

Competing interests
===================

The authors declare that they have no competing interests.

Authors' contributions
======================

SB performed a literature review and drafted the manuscript. AL drafted the manuscript. MA, LAW, and PEM managed the case and revised the manuscript critically. All authors read and approved the final manuscript.

Acknowledgements
================

SB is supported in part by the \'Programme des bourses McLaughlin du doyen de la Faculté de médecine de l'Université Laval' and the William H. Ross Fellowship in Vitreo-Retinal Excellence. AL is supported in part by the \'Programme des bourses McLaughlin du doyen de la Faculté de médecine de l'Université Laval.' The authors thank Cheyenne Johnson BNSc, RN, MPH, CCRP for assisting with the literature review and for reviewing the manuscript. Grant was received from Allergan Inc. to support the publication of this study.