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]


Studies on the effectiveness and safety of cilostazol, beraprost sodium, prostaglandin E1 for the treatment of intermittent claudication

Hashiguchi M, Ohno K, Saito R

CRD summary

This review assessed cilostazol, beraprost sodium and prostaglandin E1 (PGE1) for treating intermittent claudication to improve walking distance. The authors concluded that cilostazol and PGE1 are effective, but further studies ofberaprost sodium are needed. A narrow literature search limits the reliability of these conclusions.

Authors' objectives

To assess the effectiveness of cilostazol, beraprost sodium and prostaglandin E1 (PGE1) in improving walking distance in patients with intermittent claudication.

Searching

MEDLINE was searched for papers published in English or Japanese between January 1966 and May 2001; the search terms were reported. The reference lists of retrieved papers were checked for further studies, while experts in the field and relevant pharmaceutical companies were contacted for unpublished and ongoing trials.

Study selection

Study designs of evaluations included in the review

Specific interventions included in the review

Studies of cilostazol, beraprost sodium or PGE1 were eligible for inclusion. The included studies of cilostazol used a daily oral dose of 200 mg for between 6 and 24 weeks; studies of beraprost used a daily oral dose of 120 micrograms for either 12 weeks or 6 months; studies of PGE1 used a daily intravenous dose of 60 micrograms (either every day, 2 days per week or 5 days per week) for between 4 and 12 weeks.

Participants included in the review

Studies of adults with arteriosclerosis obliterans and a main complaint of intermittent claudication (stage II according to the Fontaine classification) were eligible for inclusion.

Outcomes assessed in the review

Studies reporting the maximum walking distance (MWD) or pain-free walking distance (PFWD), as evaluated using a treadmill test, were eligible for inclusion. Adverse event outcomes were also included in the review.

How were decisions on the relevance of primary studies made?

Two reviewers independently assessed studies for inclusion.

Assessment of study quality

The studies were assessed using a scoring system developed by Chalmers. The scoring system considered the following factors within 30 items: study hypothesis, participant selection, participant characteristics, sample size, randomisation and blinding, outcome definition and measurement, and statistical methods. The scoring for each item allowed a maximum total score of 100. The studies were classed as high quality (more than 70 points), moderate quality (40 to 69 points), or low quality (less than 40 points). Three reviewers independently assessed study quality, with any differences resolved by consensus.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. The mean value and standard deviation were extracted for MWD and PFWD at baseline, and for changes immediately following the treatment period, at 4 weeks after the commencement of treatment, and at the end of the maximum follow-up period after treatment. The number of participants experiencing adverse events was also extracted for each study and used to calculate the odds ratio (OR) with 95% confidence intervals (CIs).

Methods of synthesis

How were the studies combined?

Studies rated as moderate or high quality were combined using meta-analysis, employing a fixed-effect model with studies weighted by sample size, to derive pooled effect sizes and 95% CIs for each drug and outcome. For MWD and PFWD, the weighted mean difference (WMD) was calculated using the general variance method; for adverse events, the pooled OR was estimated using the Mantel-Haenszel method. If statistical heterogeneity was detected, the pooled estimate was calculated using a random-effects model (DerSimonian and Laird) instead.

How were differences between studies investigated?

Statistical heterogeneity was assessed using the Q statistic with a P-value of less than 0.05 judged to be statistically significant.

Results of the review

The review included 11 RCTs (n=2,131).

All 11 studies were rated as being of moderate quality, with scores ranging from 54 to 66.

Cilostazol (6 RCTs, 1,352 participants).

Effectiveness: at the end of the treatment period (ranging from 12 to 24 weeks), cilostazol had a significantly greater effect than placebo on both the MWD (WMD +52.19 m, 95% CI: 32.08, 72.31; 5 RCTs) and PFWD (WMD +39.75 m, 95% CI: 23.39, 56.10; 3 RCTs). Similar smaller, but still statistically significant, effects were seen 4 weeks into treatment (3 RCTs). Only one RCT reported follow-up after the end of treatment. This trial found no significant effect of cilastazol over placebo 6 weeks after active treatment ceased.

Adverse events: the drop-out rate was significantly higher in the cilostazol group than in the placebo group (OR 1.98, 95% CI: 1.27, 3.07; 5 RCTs). The death rates were similar in the cilostazol and placebo groups (5 RCTs; 0.7% in each group), and there was no significant difference between the groups in the rate of serious adverse events (4 RCTs). Adverse effects that were more common in those taking cilostazol included headache, dizziness, palpitation, diarrhoea and abnormal stool.

Beraprost (2 RCTs, 505 participants).

Effectiveness: one RCT reported changes in MWD and PFWD after 12 weeks; these were not statistically significantly greater in the beraprost group than in the placebo group.

Effectiveness: at the end of the treatment period (4 weeks in 2 RCTs, 8 weeks in the other), PGE1 had a significantly greater effect than placebo on both the MWD (WMD +100.27 m, 95% CI: 15.76, 184.78; 3 RCTs) and PFWD (WMD +55.73 m, 95% CI: 21.54, 89.92; 3 RCTs). The results were similar when the analysis was at 4 weeks. Two RCTs reported follow-up after the end of treatment (one after 12 weeks and the other after 8 weeks), but found no benefit of PGE1 over placebo for either MWD or PFWD.

Adverse events: no serious adverse events were reported (3 RCTs). There were no significant differences between PGE1 and placebo for reddening of infusion vein (1 RCT), hypotension (1 RCT), or diarrhoea or nausea (1 RCT).,

Cost information

The drug cost (in Japanese yen, Y) per metre increase of PFWD was calculated to be Y 1,124 for cilostazol, Y 750 for beraprost and Y 8,036 for PGE1.

Authors' conclusions

Cilostazol and PGE1 can be considered effective for the treatment of intermittent claudication. Further studies are needed to clarify the efficacy of beraprost sodium.

CRD commentary

The review question and inclusion criteria were clearly defined. The search used only one electronic database and, although other methods were used to locate published and unpublished studies, some relevant literature might have been missed (as the authors acknowledged). The inclusion of only papers in Japanese and English also raises the possibility of language bias. More than one reviewer performed the study section and quality assessment, which should have minimised the introduction of errors and bias during these processes. Study quality was formally evaluated, and the fact that the studies had to meet a certain level of quality to be included in the analysis should enhance the reliability of the results of the review.

The decision to pool studies using a meta-analysis might not have been appropriate for the PGE1 studies, as the use of the random-effects model meant that statistical heterogeneity was detected. Furthermore, the authors stated that the studies, in general, were also clinically heterogeneous in terms of the treatment period, disease status of participants and treadmill conditions; this makes direct comparisons questionable. The conclusions of the review follow from the results presented. However, the narrow literature search and small number of heterogeneous studies analysed, particularly for PGE1, limits the reliability of the conclusions.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that further research is needed to clarify the efficacy of beraprost sodium and to assess limaprost alfadex (an oral formulation of PGE1).

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.