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]


Key PointsTo our knowledge, there is no comprehensive review on oncoviruses other than EBV associated with gastric cancer risk.Positive findings might be helpful to suggest further mechanism investigation and high-risk subpopulation recommendation.The major difficulty of this systematic review might be the lack of relevant researches on this topic.Meta-analysis might be impossible due to limited published data, or diverse detection methods.Despite of any positive association, the causative function of the specific oncovirus may still not be evidenced due to small-scaled observations, or complex and underestimated confounders.

1. Introduction
===============

Gastric cancer is one of the leading mortality malignancies worldwide,^\[[@R1]\]^ and caused 782,685 deaths according to the GLOBOCAN 2018 fact sheet.^\[[@R2]\]^ The 5-year overall survival of gastric cancer is fairly poor worldwide,^\[[@R3]\]^ since most countries do not establish a nationwide gastric cancer screening program for the high-risk subpopulation, except Japan and Korea.^\[[@R4]--[@R6]\]^ The difficulty in early detection and treatment at early stage is still a comprehensive issue to improve population survival outcome of gastric cancer.^\[[@R7],[@R8]\]^ Currently, it keeps no definitely efficient biomarker or combinations to identify gastric cancer cases for the sake of the early detection.^\[[@R9],[@R10]\]^ Therefore, the necessity of identifying exposure factors associated with the gastric cancer risk is underlined. It may be helpful to organize the screening, prevention, and surveillance program for the high-risk subpopulation of gastric cancer.

As the World Health Organization suggested, gastric cancer is one of the infection associated malignancies, and therefore it could potentially be prevented and early detected among high-risk subpopulation.^\[[@R11]--[@R13]\]^ Helicobacter pylori (Hp) has been regarded as a biological risk factor for the carcinogenesis of gastric epithelium,^\[[@R14],[@R15]\]^ especially highly associated with non-cardia gastric adenocarcinoma.^\[[@R16],[@R17]\]^ Epidemiological data support Hp as the most important biological risk factor for gastric cancer in both Western and Eastern countries.^\[[@R18]--[@R20]\]^ Epstein-Barr virus (EBV) is very common among general population, and has also been known to be present in a small proportion of gastric cancer tissues.^\[[@R21]\]^ Some meta-analyses have concluded that EBV-positive gastric cancer might appear in 6.9% to 8.8% of all gastric cancer patients.^\[[@R22]--[@R25]\]^

Therefore, it is questionable whether any other oncovirus other than EBV would be associated with human gastric cancer risk. We will perform a systematic review and meta-analysis to estimate the associations of human gastric cancer risk with viral infection, in addition to EBV, based on epidemiological studies.

2. Methods
==========

2.1. Search strategy
--------------------

The PubMed database will be searched up to Dec 31, 2018, using the following search algorithm (("stomach neoplasms"\[MeSH Terms\] OR ("stomach"\[All Fields\] AND "neoplasms"\[All Fields\]) OR "stomach neoplasms"\[All Fields\] OR ("gastric"\[All Fields\] AND "cancer"\[All Fields\]) OR "gastric cancer"\[All Fields\]) AND ("viruses"\[MeSH Terms\] OR "viruses"\[All Fields\] OR "virus"\[All Fields\])) NOT ("animal"\[Filter\] OR "review"\[Publication Type\] OR "case reports"\[Publication Type\] OR "letter"\[Publication Type\] OR "comment"\[Publication Type\]). The search was limited to studies in humans. There is no limitation of publication language.

2.2. Eligibility
----------------

The eligible studies compared the positivity of any oncovirus between cases with histologically proven gastric cancer to healthy or nonmalignant controls. The patients with gastric lymphoma, gastrointestinal stromal tumor, and squamous cell carcinoma are ineligible. Any type of cohort study, cross-sectional study, or case-control study can be considered. The detection of viruses was performed in cases and controls based on either blood/serum or tissue specimens. Any targeted virus other than EBV are eligible in this systematic review. With the only particular exception, EBV was not additionally considered in this systematic review, because it had been comprehensively assessed yet in the our previous study through the similar methodology as the first part of serial reviews.^\[[@R21]\]^ There is no limitation on the race, sex, age, cancer stage, and the treatment strategy. Only those studies with extractable data will be considered for analysis.

2.3. Selection and quality assessment
-------------------------------------

Two reviewers will separately browse the titles/abstracts, and assess the potentially eligible full-texts, according to the predefined inclusion and exclusion criteria. Discrepancies will be resolved by consensus with a third reviewer. Risk of bias assessment of all included studies is to be independently performed by 2 reviewers, according to the Newcastle-Ottawa Scale (NOS).^\[[@R26]\]^ The scale contains 8 criteria of 3 categories to evaluate the sample selection, comparability on the bases of design or analysis, outcome assessment.

2.4. Data extraction
--------------------

Extracted items includes general study characteristics (year, country, study design), characteristics of the study population (size, sex, age, disease related factors), and types of measurements (specimen types, analytic procedures). Number of cases and controls will be extracted from publications or calculated from the reported percentage of cases. Potential discrepancies in extracted items if any will be resolved by further review and discussion.

2.5. Statistics
---------------

The Cochrane Reviewer Manager (RevMan) 5.3 (Copenhagen, Denmark), the STATA 12.0 softwares (Texas), and the PASS 11 (Utah) will be used for statistical analysis, where applicable.^\[[@R27]--[@R29]\]^ All analysis will be based on individual oncovirus. If quantitative combination is impossible, narrative review will be considered. The pooled prevalence of any oncovirus infection in gastric cancer patients and healthy controls will be combined in meta-analysis for rate, with 95% confidence intervals (CIs). The pooled odds ratios (ORs) and their 95% CIs for oncovirus prevalence will be calculated between gastric cancer patients and healthy controls by fixed or random effect model where suitable. The Mantel-Haenszel test or the DerSimonian-Laird test is to be used for fixed or random model respectively. Two-sided *P* values for the pooled ORs \<0.05 is considered as statistical significance. I-square will be estimated to evaluate the heterogeneity of meta-analyses. If the *P* values of heterogeneity test \<.1, random effect model should be considered. Funnel plots will be drawn by the STATA 12.0 software to evaluate the publication bias.^\[[@R28]\]^ Both the continuity corrected Begg rank correlation test and Egger linear regression test will be used.^\[[@R30]\]^ Any *P* value \<.05 of Begg or Egger test is considered as significance of publication bias. In Egger test, the intercept and its 95% CI will be estimated. In sensitivity analysis, the leave-one-out method will be applied for those meta-analyses pooling at least 2 studies. Additionally, L'Abbé plot and Galbraith plot will be observed the heterogeneity. For an individual study, the power (1--β) will be estimated by the PASS 11 software.^\[[@R29]\]^ The category of 2 independent proportions to test inequality is selected, and parameter module of proportions is used for calculation.^\[[@R31]\]^ Two-sided Z test (pooled) is provided with *α* = 0.05. Additional sensitivity analysis will be performed by excluding the studies with the power \<0.70 or \<0.80.

2.6. Registration
-----------------

The present systematic review (registration number: CRD42015029703) was registered in the PROSPERO International Prospective Register of Systematic Reviews supported by the National Institute for Health Research of the National Health Service (NHS), UK.^\[[@R32]\]^

2.7. Patient and public involvement
-----------------------------------

This review worked with the literature and will not directly involve human beings or animals. This study is a joint with the Sichuan Gastric Cancer Early Detection and Screening (SIGES) research project.^\[[@R33]\]^

2.8. Ethics and dissemination
-----------------------------

The protocol was not submitted for any ethical approval due to the literature-based nature. The results of this study will be published in a peer-reviewed academic journal and presented at academic conferences.

2.9. Reporting
--------------

This meta-analysis were conducted according to the MOOSE 2000 statements,^\[[@R34]\]^ and a flow diagram is to be plotted.^\[[@R35]\]^

3. Discussion
=============

Gastric cancer has been documented that is associated with the infection of Hp or EBV. Till now, Hp infected persons are suggested as high-risk subpopulation of gastric cancer development.^\[[@R13],[@R20]\]^ In Japanese and Korean gastric cancer control programme, massive screening and eradication of Hp infection is organized and integrated into early gastric cancer detection.^\[[@R36]--[@R39]\]^ Early detection and eradication of Hp might decrease the incidence of gastric cancer,^\[[@R40]\]^ rather than in the stages of mucosal precancerous lesions.^\[[@R41]\]^ This is a successful attempt of a pathogen based gastric cancer control. Although the causative association was highly considered between gastric cancer risk and EBV infection,^\[[@R21]\]^ a plan of EBV based gastric cancer control has not been established yet. Moreover, in the cancer genome atlas investigation, EBV-positive gastric cancer has been clearly identified as a specific type of molecular classification.^\[[@R1]\]^ Therefore, pathogen guided gastric cancer research on mechanism or population screening, prevention and treatment would be a potentially important opportunity.

Besides, several other oncoviruses are considered to be associated with human cancers.^\[[@R42]\]^ For instance, some high-risk, oncogenic types of human papillomavirus (HPV) are able to result in cervical cancer, as well as potentially anal and colorectal cancer.^\[[@R43]--[@R45]\]^ In the 2009, the WHO recommended the HPV vaccination targeting young girls before the onset of sexual activity as a national immunization programs.^\[[@R46]\]^ At the early of the 2014, 21 European countries have included HPV vaccination for girls in their national immunization schedules, and 11 out of those countries have also introduced catch-up programs.^\[[@R47]\]^ Besides, a cost-effectiveness analysis in Denmark found the inclusion of both boys and girls is a cost-effective preventive approach to control cancers and cancer precursors in men and women.^\[[@R48]\]^ The potential association between HPV and gastric cancer risk would be interesting to studied in the present systematic review.

Similarly, hepatitis B virus (HBV) has been classified a causative pathogen for primary liver cancer, which had high incidence and mortality in China.^\[[@R49]\]^ Certain estimate suggested 60% to 80% primary liver cancers were the consequence of HBV infection and related chronic hepatitis.^\[[@R50]\]^ Therefore, since the 1992, massive newborn and pediatric HBV vaccination programme was started.^\[[@R6]\]^ Along with the decrease of HBV prevalence nationwide and expectation of below 1% according to the governmental estimate,^\[[@R51]\]^ the incidence and mortality of primary liver cancer would be hoped to controlled correspondingly. Interestingly, a case-control study found a potential association between HBV seropositivity (hepatitis B surface antigen) and gastric cancer risk, specially among those without family history of gastric cancer.^\[[@R52]\]^ However, the association was quite challenging, as the positivity of HBV DNA in gastric cancer tissues was only 0% to 3% and no direction evidence of HBV DNA detected in gastric cancer cells.^\[[@R53]\]^ This present systematic review will pay attention to the association between HBV and gastric cancer risk.

In addition, there are some other oncoviruses, such as HCV, JCV, CMV, BKV, SV40, HSV, and VZV, etc, will also be considered for evaluation, if possible. However, the major difficulty of this systematic review might be the lack of relevant researches on this topic. Meta-analysis might be impossible due to limited published data, or diverse detection methods. Despite of any positive association, the causative function of the specific oncovirus may still not be evidenced due to small-scaled observations, or complex and underestimated confounders.

In a short, this systematic review and meta-analysis might be informative to identify or deny certain oncoviruses which are candidates of risk factor for gastric cancer. To our knowledge, there is currently no comprehensive review on oncoviruses other than EBV associated with gastric cancer risk. Positive findings might be helpful to suggest further mechanism investigation and high-risk subpopulation recommendation.

Acknowledgments
===============

The work is a joint with the Sichuan Gastric Cancer Early Detection and Screening (SIGES) research project. The authors thank the substantial work of Volunteer Team of Gastric Cancer Surgery (VOLTGA), West China Hospital, Sichuan University, China.

Author contributions
====================

**Conceptualization**: Xin-Zu Chen.

**Data curation:** Rui Wang, Xin-Zu Chen.

**Formal analysis**: Xin-Zu Chen.

**Funding acquisition**: Xin-Zu Chen.

**Investigation:** Rui Wang, Kai Liu, Xin-Zu Chen.

**Methodology:** Xin-Zu Chen.

**Project administration**: Rui Wang, Kai Liu.

**Resources:** Xin-Zu Chen.

**Supervision:** Xin-Zu Chen.

**Validation:** Rui Wang, Kai Liu, Xin-Zu Chen.

**Writing -- original draft**: Xin-Zu Chen.

**Writing -- review & editing**: Xin-Zu Chen.

Rui Wang orcid: 0000-0003-0101-4431.

Kai Liu orcid: 0000-0002-7584-9231.

Xin-Zu Chen orcid: 0000-0002-7619-6244.

Abbreviations: BKV = BK virus, CI = confidence interval, CMV = cytomegalovirus, EBV = Epstein-Barr virus, HBV = hepatitis B virus, Hp = Helicobacter pylori, HPV = human papillomavirus, HSV = herpes simplex virus, JCV = JC polyoma virus, NOS = Newcastle-Ottawa Scale, OR = odds ratio, SIGES = Sichuan Gastric Cancer Early Detection and Screening research project, SV40 = simian vacuolating virus 40, VZV = Varicella-Zoster virus.

RW and KL have contributed equally as co-first authors.

Wu Jieping Medical Foundation (No. 320.2710.1815) for XZC. The funder has no role in the conception and performance.

The authors have no conflicts of interest to disclose.