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]


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Introduction
============

Appendicitis is the most frequently encountered acute condition requiring surgical management in children and adults \[[@REF1]-[@REF3]\]. In about 30% of pediatric patients, making an accurate diagnosis can be challenging \[[@REF2]-[@REF3]\]. Unfortunately, there is a fine line between sending someone for potentially unnecessary invasive surgery versus risking the detrimental complications of untreated appendicitis. However, due to the untreated risk of perforation, abscess formation, bowel obstruction, peritonitis and sepsis \[[@REF3]\], up to 20% negative appendectomy rate is considered acceptable in adults and children \[[@REF4]-[@REF5]\].

In order to prevent misdiagnosis of acute appendicitis (AA), ultrasound (US) and computed tomography (CT) are being heavily relied upon to aid in making the correct diagnosis \[[@REF3],[@REF6]\]. CT scan has better overall sensitivity and specificity for diagnosing AA compared to US \[[@REF6]-[@REF7]\], with documented sensitivity and specificity ranging from 95% to 97% and 94% to 97%, respectively \[[@REF8]-[@REF9]\]. The dilemma of using CT in pediatric patients stems from the exposure of ionizing radiation. Children are approximately 10 times more sensitive to ionizing radiation compared to adults \[[@REF1],[@REF10]\], thus increasing their risk of developing cancer in the future \[[@REF11]-[@REF12]\]. Although magnetic resonance imaging (MRI) has shown similar results to CT with the advantage of not exposing the patient to ionizing radiation \[[@REF1],[@REF13]\], its biggest drawback remains a relatively high cost, availability and prolonged acquisition times with the use of general anesthesia in the pediatric age group. Thus, US is the preferred first-line diagnostic imaging for evaluation of AA in pediatric patients \[[@REF3]-[@REF4],[@REF6]\].

US provides a non-invasive, readily available, and cost-effective way of diagnosing AA without exposing the patient to ionizing radiation. However, the accuracy of US has varied widely in the literature. This is secondary to the appendix visualization rate, which ranges from 40% to 89% \[[@REF3],[@REF8],[@REF14]-[@REF15]\]. US can be as accurate if not more as CT if the appendix is visualized. Factors that play a role in appendix visualization include operator experience (seasoned technologist, pediatric radiologist versus general radiologist), patient body habitus and anatomical position of the appendix.

Secondary signs (SS) have been claimed to be useful when the appendix is not visualized and AA is still suspected. These are anatomical descriptions of inflammation within the surrounding tissue caused by AA. There is a paucity of data as to how valuable SS can be in terms of type and number. Thus, the purpose of our study is to shed further light on the utility of US and its SS in diagnosing AA.

Materials and methods
=====================

The study was approved by the Ethics Review Committee of our institute and the need for informed consent was waived. We conducted a retrospective review to determine the accuracy of US in the diagnosis of AA in the pediatric population and to evaluate the utility of SS in cases where the appendix was not visualized. The study was conducted at the Aga Khan University Hospital, a tertiary care center located in the heart of the largest metropolitan city in the country. Subjects aged from two to sixteen years who had undergone US right lower quadrant (RLQ) for acute abdominal pain with clinical suspicion for AA, were retrieved from the departmental database from June 15, 2003 to December 9, 2016.

Patients were excluded if they had primary and/or SS of appendicitis on US without CT or biopsy confirmation. Also excluded were patients whose indication was to evaluate an already known condition and those who were status post appendectomy. Patients with negative US RLQ (no primary and SS of AA) were included regardless of a confirmatory CT or biopsy. 

The graded compression technique described by Puylaert \[[@REF16]\] (according to our departmental protocol) was used and all examinations were performed using Toshiba Xario (Toshiba Medical Systems Corporation, Japan) with 3.5-10 MHz probes. Board certified radiologists performed US during the day and third and fourth year (senior) radiology residents performed US overnight. All US images and reports were finalized by board certified radiologists with experience ranging from three to 26 years.

Data were transcribed from the hospital\'s medical record system. This included US findings with corresponding CT scan and histopathology results when present and patient demographics. US reports were retrospectively classified into three groups by the principal investigator: Group 1 included all patients with a normal appendix or if the appendix was not visualized, no SS were present. Patients were classified into Group 2 if the appendix was not clearly seen and they had one or more SS of AA. Group 3 included all patients with primary signs of AA. 

Primary signs of AA were defined as a blind-ending loop measuring greater than or equal to 6 mm in diameter, demonstrating any of the following features: non-compressibility, aperistalsis, increased wall thickness and vascularity. The following SS were recorded: free fluid (reports with mild free fluid were excluded as this is a normal finding), lymph node greater than or equal to 8 mm in diameter, echogenic fat in the RLQ, decreased peristalsis, omental thickening, RLQ collection, cecal thickening and appendicolith. CT and histopathology (biopsy) criteria were either positive (AA) or negative (normal appendix).

The diagnostic accuracy of US and SS for AA was determined using the standard epidemiological method of calculating the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The number of SS was correlated with the presence of AA. Statistical analysis was obtained using the Statistical Package for Social Sciences (SPSS) software version 21 (IBM, Armonk, NY, USA).

Results
=======

Our database yielded 1179 cases of suspected AA between the ages of two and sixteen years. Among these, 22 patients from Group 2 and 34 patients from Group 3 did not have CT or biopsy confirmation, and were therefore excluded. Another eight patients were excluded either because the appendix had been surgically removed or their indication for US was to evaluate another known entity. The final sample size was 1115 of which 714 were males and 401 were females. The mean age was 9.4 years. Three hundred and fifty eight (29%) patients had AA confirmed by CT and/or biopsy. Three hundred and eighty patients underwent appendectomy of which 89% (337/380) had AA and therefore, the negative appendectomy rate was 11% (43/380).

To calculate the accuracy of US RLQ for AA, we considered Group 1 to be negative and Group 2 and Group 3 as positive. Using this classification method, the sensitivity was 79%, specificity 97%, PPV was 93%, NPV was 91% and the overall accuracy was 91% (Table [1](#TAB1){ref-type="table"}).

###### Accuracy of ultrasound classification for acute appendicitis

PPV: positive predictive value; NPV: negative predictive value

  ---------------------------------------------------------------------------------------------------------------------------- -----------------
  Parameter                                                                                        Percentage (Total number)   
  Sensitivity                                                                                                                  79% (283/358)
  Specificity                                                                                                                  97% (735/757)
  PPV                                                                                                                          93% (283/305)
  NPV                                                                                                                          91% (735/810)
  Accuracy                                                                                                                     91% (1018/1115)
  ---------------------------------------------------------------------------------------------------------------------------- -----------------

Group 1 included patients in whom the appendix was normal or if the appendix was not seen, there were no primary or SS of AA (n=810, 73%). Among these, 735 (91%) did not have AA. There were 52 (5%) patients with SS in the absence of a visualized appendix in Group 2. Appendicitis was present in 38/51 (75%) patients and three patients had a negative appendectomy. In Group 3, there were 254 (19%) patients who had primary signs of AA. Out of the 254, 245 (96%) patients were confirmed to have AA. Among the 43 patients with a negative appendectomy, Group 3 had 11 (Table [2](#TAB2){ref-type="table"}).

###### Confirmed appendicitis (computed tomography + biopsy) and negative appendectomy (biopsy)

  ----------------------- ------- ------------------------------------------------------------------------------ ----------------------------------------------------------- ------------------------------
                          Total   Group 1 (n=810) Normal appendix or appendix not seen, absent secondary signs   Group 2 (n=52) Appendix not seen, secondary signs present   Group 3 (n=253) Appendicitis
  Appendicitis            358     75 (9%)                                                                        38 (75%)                                                    245 (96%)
  Negative appendectomy   43      29                                                                             3                                                           11
  ----------------------- ------- ------------------------------------------------------------------------------ ----------------------------------------------------------- ------------------------------

A total of 68 SS were noted in the 52 patients of Group 2. The most frequently encountered SS was enlarged lymph node (n=21), and AA was present in 86% (18/21) of these patients. Echogenic fat in the right iliac fossa was the second most common SS and was seen in 15 patients, and 10 (67%) had AA. 10 patients had decreased peristalsis of which seven (70%) had AA. There were eight patients with free fluid exceeding physiological amounts, per the discretion of the radiologists, six (75%) of these patients had AA. A collection was visualized in seven patients of which five (71%) had AA. Cecal thickening/edema was present in three patients, all of whom had AA (100%). There was appendicolith in two patients, both had AA (100%), whilst omental thickening was also seen in two patients, only one had AA (50%) (Table [3](#TAB3){ref-type="table"}).

###### Accuracy of secondary ultrasound findings for appendicitis

PPV: positive predictive value; NPV: negative predictive value; RLQ: right lower quadrant

  -------------------------------- ------- -------------- ------------- ------------- ------ ----- ----------
  Secondary Sign                   Total   Appendicitis   Sensitivity   Specificity   PPV    NPV   Accuracy
  Lymph nodes                      21      18             19%           100%          86%    91%   91%
  Echogenic fat (RLQ)              15      10             12%           99%           67%    91%   90%
  Decrease peristalsis             10      7              9%            100%          70%    91%   90%
  Free fluid (moderate to large)   8       6              7%            100%          75%    91%   91%
  Collection                       7       5              6%            100%          71%    91%   91%
  Cecal thickening/edema           3       3              4%            100%          100%   91%   91%
  Appendicolith                    2       2              3%            100%          100%   91%   91%
  Omental thickening               2       1              1%            100%          50%    91%   91%
  -------------------------------- ------- -------------- ------------- ------------- ------ ----- ----------

There were 40/52 patients with only one SS, and AA was found in 28 (70%) of these patients. Two SS were seen in nine out of 52 patients of whom seven (78%) had AA. Three and four SS were seen only in two and one patients respectively, all of whom had AA (100%) (Table [4](#TAB4){ref-type="table"}).

###### Relationship between number of secondary signs and appendicitis

  ----------------------- ------- -------------- ------------
                          Total   Appendicitis   Prevalence
  One secondary sign      40      28             70%
  Two secondary signs     9       7              78%
  Three secondary signs   2       2              100%
  Four secondary signs    1       1              100%
  ----------------------- ------- -------------- ------------

The overall perforation rate was 10% (n=36) of which 28% (10/36) were detected on US. There were five perforations in Group 1, Group 2 had eight, and Group 3 had the most with 23 (Table [5](#TAB5){ref-type="table"}). There was one US RLQ that was false positive for perforation although the patient did have AA on biopsy.

###### Utility of ultrasound for perforations

US: ultrasound

  ---------------------------- ------- ------------------------------------------------------------------------------ ----------------------------------------------------------- -------------------------------
                               Total   Group 1 (n=810) Normal appendix or appendix not seen, absent secondary signs   Group 2 (n=52) Appendix not seen, secondary signs present   Group 3 (n=253)  Appendicitis
  Perforations                 36      5                                                                              8                                                           23
  Perforation detected by US   10      0                                                                              3                                                           7
  ---------------------------- ------- ------------------------------------------------------------------------------ ----------------------------------------------------------- -------------------------------

Discussion
==========

Our study corroborates that US should be used as first-line imaging for suspected appendicitis in children and that SS has a strong potential to aid in making in the correct diagnosis \[[@REF3],[@REF7]\]. The prevalence of AA in our study was 29% which is similar to other reported studies (25%, 32%, 34%). Our US accuracy of 91% for diagnosing AA in pediatric patients was also comparable with prior studies \[[@REF3]-[@REF4],[@REF7],[@REF14],[@REF17]\].

Despite our acceptable results, 91 patients were incorrectly diagnosed. Lack of appendix visualization is the most important factor. There are many factors that can contribute to lack of appendix visualization such as; imaging a spontaneously resolving appendicitis, inability to detect early AA, operator experience, patients' physique; pain status and sensitivity, location of the appendix and high patient volume setups resulting in shorter scan times for locating the appendix \[[@REF7],[@REF17]\]. Unfortunately, many of these factors are out of one\'s control which is also why surgeons sometimes overlook imaging results if they don\'t correlate with clinical parameters \[[@REF18]\]. Based on our experience, if the appendix is not visualized and no SS are present, we believe that the patient should be managed operatively if there is high clinical suspicion \[[@REF3]\].

The presence of appendicitis without primary or secondary signs was 9%, slightly higher compared to 7.1% obtained in the study by Estey et al. \[[@REF3]\], whilst Wiersma et al. \[[@REF7]\] had none but their sample size was 212 compared to our 1115. Despite this, our NPV was greater than 90% which is concordant with prior studies \[[@REF14]\].

In our study, only 4.7% (52) patients had SS in the absence of a visualized appendix. The prevalence of this group in the literature ranges from 3%-45% \[[@REF3]-[@REF4],[@REF14]\]. The major issue with SS is that they are not sensitive. Furthermore, most patients will only have one to two SS if any at all, and in our opinion, these patients pose the greatest diagnostic dilemma. However, in our study certain SS such as cecal thickening and the presence of appendicolith had a 100% PPV. RLQ echogenic fat, decreased peristalsis, free fluid and collection had a reasonable PPV ranging 67-75% (Figure [1](#FIG1){ref-type="fig"}). Although the presence of three or more SS is very uncommon \[[@REF3],[@REF14]\] we felt appendicitis could be confidently diagnosed in this patient group (three patients - all had AA). 

![Sonographic images of a 10-year-old male\
A heterogenous collection with moving internal echoes (arrow) was noted in the right iliac fossa with echogenic inflammation of the surrounding fat (arrowheads). The appendix was not separately visualised. This patient had perforated appendicitis, which was confirmed on surgery.](cureus-0010-00000003779-i01){#FIG1}

The perforation rate among patients with AA was 10.1%. The highest percentage of perforations was found in Group 2 (20.1%), similar to Wiersma et al. \[[@REF7]\]. This is because a perforated appendix is relatively difficult to visualize. Group 1 and Group 3 had a perforation rate of 6.7% and 9.4%, respectively.

Methods to standardize the US reporting system with the inclusion of SS have shown to improve patient management. A study conducted by Partain et al. demonstrated that the use of a standardized US reporting system coupled with increased reporting of SS resulted in a decreased use of CT and lowered the admission rate for observation of patients with suspected AA and equivocal US results \[[@REF8]\]. Larson et al. proposed a five-category interpretive scheme based on appendix visualization, which allowed for more specific guidance for clinical and surgical management potentially reducing the number of negative appendectomies and providing superior confidence in the interpretation of cases where the appendix was not seen \[[@REF19]\].

There are several limitations in our study. Firstly, it is a retrospective study and therefore carries associated limitations. Secondly, which we feel is the most problematic limitation and also seen in other similar studies, is the relatively low number of patients with SS. Additionally, there is no way of truly knowing whether a patient that presented with US was truly negative without histopathology. There is also a lot of variability in results due to factors such as operator experience. Hence, larger multicentric prospective studies are required ideally using standardized reporting algorithms to further determine how individual SS and a combination of SS correlate with AA.

Conclusions
===========

US should always be used as first line for the diagnosis of AA in pediatric patients. SS have the key potential to aid in making an accurate diagnosis when the appendix is not visualized. In our study, equivocal cases with the presence of three or more secondary signs had a high probability index for AA. However, more research in the form of a prospective study is needed for evaluation of how secondary signs either individually or collectively can further aid the radiologist to make an accurate diagnosis. 

The authors have declared that no competing interests exist.

Consent was obtained by all participants in this study. Ethics Review Committee, The Aga Khan University issued approval 4600/RAD/17

**Animal subjects:** All authors have confirmed that this study did not involve animal subjects or tissue.