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The S TEST Reagent Cartridge Carbon Dioxide (CO2) is intended for the quantitative determination of carbon dioxide concentration in serum or lithium heparin plasma using the HITACHI Clinical Analyzer E40. Carbon dioxide measurements are used in the diagnosis and treament of numerous potentially serious disorders associated with changes in body acid-base balance. The S TEST Reagent Cartridge Carbon Dioxide (CO2) is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available. The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H). System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge Carbon Dioxide.

The provided text describes the 510(k) summary for the Hitachi S TEST Reagent Cartridge Carbon Dioxide (CO2), a device for quantitative determination of carbon dioxide concentration in serum or lithium heparin plasma. The document focuses on demonstrating the substantial equivalence of this device to a legally marketed predicate device (Carbon Dioxide L.3K Assay, Sekisui Diagnostics, PEI, Inc., Canada- K042362) through nonclinical and clinical performance studies.

Here's an analysis of the acceptance criteria and the studies conducted:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a table of "acceptance criteria" but rather describes the performance characteristics tested and their results, often comparing them to the predicate device or established standards. I will infer acceptance criteria based on standard clinical chemistry performance requirements and the described study outcomes.

• Low (10.11 mmol/L): 1.3% (4.4%)
• Middle (19.41 mmol/L): 1.3% (3.7%)
• High (33.06 mmol/L): 1.2% (3.7%) |
  | Precision (External POL Study) | Similar to in-house, %CVs within acceptable clinical limits. | Total %CV (n=30 for each level at each site)
• Site 1: 4.1% (Low), 4.8% (Mid), 3.2% (High)
• Site 2: 6.0% (Low), 4.4% (Mid), 3.7% (High)
• Site 3: 3.1% (Low), 1.9% (Mid), 3.7% (High) |
  | Interference | Recoveries between 90% and 110% of the neat value in the presence of interferents. | No interference from Lipemia (up to 1,000 mg/dL Intralipid), Ascorbic acid (up to 50 mg/dL), Hemoglobin (up to 1,000 mg/dL), Unconjugated bilirubin (up to 19.1 mg/dL) |
  | Method Comparison (Accuracy) | Strong correlation (r > 0.95), slope close to 1, y-intercept close to 0, and agreement with predicate/reference method. | In-house (vs. standard lab system): n=96, r=0.981, Slope=1.03 (0.97-1.08), y-intercept=0.98 (-0.17-2.12)
  External POL Study (vs. comparative method):
• Site 1: n=47, r=0.984, y=0.91x+1.49 (Slope CI: 0.87-0.95, Intercept CI: 0.67-2.32)
• Site 2: n=45, r=0.970, y=0.92x+0.56 (Slope CI: 0.80-1.04, Intercept CI: -2.31-3.43)
• Site 3: n=47, r=0.982, y=0.92x+0.79 (Slope CI: 0.87-0.97, Intercept CI: -0.43-2.01) |
  | Matrix Comparison (Serum vs. Plasma) | Strong correlation between serum and plasma results (r > 0.95), slope close to 1, y-intercept close to 0. | n=50, r=0.980, Slope=1.00 (0.94-1.05), y-intercept=-0.34 (-1.97-1.30) |
  | Stability (Shelf Life) | Claimed shelf life supported by real-time stability data. | Supported shelf life of 6 months at 2-8°C (real-time testing ongoing). |
  | Reportable Range | Match clinical requirements; within demonstrated linearity. | 5.0 to 40.0 mmol/L (Predicate: 2.9 to 50.0 mmol/L) |
  | Detection Wavelength | Not an acceptance criterion for performance, but a technical specification. | 405/508 nm (Predicate: 405/415 nm) |

2. Sample Size Used for the Test Set and Data Provenance

• Analytical Sensitivity (LoD/LoQ): 60 replicates of reagent blank and three low samples. Three low-level specimens in six runs with three instruments over three days for LoQ.
• Linearity: 10 serial dilutions plus zero standard (n=11), assayed in duplicate.
• Precision (In-house): Three levels of serum-based commercial controls, each tested in two runs, twice a day, for 20 days.
• Interference Testing: Two serum pools with approximately 17 and 30 mmol/L carbon dioxide.
• Method Comparison (In-house): 96 clinical specimens (including 3 spiked and 3 diluted samples).
• Matrix Comparison: 50 matched serum/plasma samples (including 2 spiked and 4 diluted samples).
• Precision (External POL Study): Three blinded serum samples (low, middle, high CO2 concentrations). Each sample assayed six times per day for five days, reporting 30 results per level per site.
• Method Comparison (External POL Study): 47 serum specimens (including three spiked and four diluted samples) per site (Site 2 used 45 samples due to 2 below dynamic range).

Data Provenance:

• The studies were performed by Hitachi Chemical Diagnostics, Inc. ("in-house") and at three external Physician Office Laboratory (POL)-type sites.
• Specific countries of origin for the clinical specimens are not explicitly stated, but the company address is Mountain View, CA, USA, and POL studies suggest U.S. clinical settings.
• The studies appear to be prospective for the purpose of validating the device's performance characteristics.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not specify the number or qualifications of experts used to establish "ground truth" for the test set in the traditional sense of expert consensus for diagnostic interpretation. Instead, the ground truth is established through:

• Reference Methods/Comparative Methods: In the method comparison studies, a "standard laboratory system" or "comparative method as the reference method" was used. The qualifications of the operators of these reference methods are not provided.
• Known Concentrations: For studies like linearity, precision, and interference, known concentrations (e.g., commercial controls, spiked samples, diluted samples) are used.
• Industry Standards: Adherence to CLSI (Clinical and Laboratory Standards Institute) guidelines (e.g., CLSI EP17-A2, CLSI EP-6A, CLSI EP5-A2, CLSI EP7-A2) implies reliance on established laboratory best practices for determining analytical performance.

4. Adjudication Method for the Test Set

This type of in vitro diagnostic device (IVD) performance study (analytical and clinical chemistry accuracy/precision) typically does not involve adjudication by multiple human readers in the same way an imaging or pathology study might. Instead, the device's results are compared against:

• Reference measurements: From the predicate device or a "standard laboratory system."
• Known values: For controls, linearity standards, and spiked/diluted samples.
  The document states that method comparison samples were assayed "in singleton and in a blinded fashion" (in-house) and "assayed on the Hitachi E40 Clinical Analyzer... and a comparative method as the reference method" (external POL study), implying direct comparison without a formal adjudication panel.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This type of study design is typically used for diagnostic imaging or pathology devices where multiple human readers interpret cases, and the AI's impact on their performance is assessed. For an in vitro diagnostic (IVD) device like a CO2 reagent cartridge, the evaluation focuses on analytical performance characteristics (accuracy, precision, linearity, etc.) rather than human reader improvement with AI assistance.

6. If a Standalone (i.e., algorithm only without human-in-the-loop) Performance Was Done

Yes, the studies conducted are standalone performance studies. The Hitachi S TEST Reagent Cartridge Carbon Dioxide operates as an in vitro diagnostic device on an automated analyzer (Hitachi Clinical Analyzer E40). The performance results (accuracy, precision, linearity, etc.) described are the performance of the device and its associated system without direct "human-in-the-loop" interpretive input influencing the result generation. Human operators load samples and reagents and review results, but the device itself generates the quantitative CO2 concentration.

7. The Type of Ground Truth Used

The ground truth for the performance studies was established using a combination of:

• Reference Measurement/Comparative Method: For method comparison, results from a "standard laboratory system" or "comparative method" served as the reference.
• Known Values: For analytical studies like linearity, precision, LoD, and interference, commercial controls, calibrators, and spiked/diluted samples with known or traceable concentrations were used.
• Industry Standards: Adherence to CLSI guidelines ensures that the methods for establishing ground truth for these analytical parameters align with recognized best practices in laboratory medicine.

8. The Sample Size for the Training Set

The document does not describe a "training set" in the context of machine learning or AI development. This is an IVD device providing a quantitative measurement based on a chemical reaction and photometric detection. Its underlying "algorithm" is the chemistry reaction and calculation based on Beer-Lambert Law, not a learned AI model that requires a training set. Manufacturers establish internal specifications and calibration parameters based on extensive R&D and analytical validation, but this typically does not involve an external "training set" as understood in AI/ML.

9. How the Ground Truth for the Training Set Was Established

As explained above, there is no "training set" for this type of IVD device in the AI sense. The "ground truth" for manufacturing and calibration would be established through:

• Primary Reference Materials: Traceability to primary reference standards (e.g., American Chemical Society (ACS) reagent grade sodium carbonate alkalimetric standard for CO2).
• Internal Validation: Rigorous internal testing and validation during the device's development to ensure the chemical reaction and photometric measurements yield accurate and precise results across the dynamic range.
• Quality Control: Ongoing use of quality control materials with known values to monitor performance.
  The document states, "Each lot of S TEST Reagent Cartridge Carbon Dioxide (CO2) is calibrated by the manufacturer prior to shipment using material referenced to a standard which is traceable to American Chemical Society (ACS) reagent grade sodium carbonate alkalimetric standard." This describes the process for establishing and maintaining calibration, which is akin to "ground truth" for the device's quantitative output.

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The S TEST Reagent Cartridge Total Protein (TP) is intended for the quantitative determination of TP in serum, lithium heparinized plasma, K3 EDTA plasma and sodium citrate plasma using the HITACHI Clinical Analyzer E40. The S TEST Reagent Cartridge TP is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Total protein measurements are used in the diagnosis and treatment of a variety of diseases involving the liver, kidney, or bone marrow as well as other metabolic or nutritional disorders.

The S TEST Reagent Cartridge Albumin (ALB) is intended for the quantitative determination of ALB in serum, lithium heparinized plasma, K3 EDTA plasma and sodium citrate plasma using the HITACHI Clinical Analyzer E40. The S TEST Reagent Cartridge ALB is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Albumin measurements are used in the diagnosis and treatment of numerous diseases involving primarily the liver or kidneys.

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.

The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters. calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).

System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridges TP and ALB.

Chemistry reactions: (TP) Proteins in samples react with the biuret reagent to form a purplered complex. The concentration of total protein can be determined by measuring the absorbance of the purple-red substance.

(ALB) Albumin in the sample combines with bromcresol green to form a blue-green dye conjugate. The albumin concentration is directly proportional to the color intensity and can be determined photometrically by measuring the absorbance of this resulting blue-green color.

The provided document is a 510(k) summary for the Hitachi S TEST Reagent Cartridge Total Protein (TP) and Albumin (ALB). It details the nonclinical and clinical studies performed to demonstrate the safety and effectiveness of these in-vitro diagnostic devices.

Here's an analysis of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a singular, formal table. Instead, performance characteristics are presented as results from various studies, often implicitly comparing them to the predicate device or general industry standards (e.g., CLSI guidelines). The performance characteristics are reported as the outcome of the tests performed.

Below is a table summarizing the reported device performance for both TP and ALB, drawing from the "Technological Similarities and Differences to the Predicate" section and the "Brief Description of Nonclinical Data" and "Brief Description of Clinical Data" sections. Implicit acceptance is typically shown by these results being deemed "safe and effective for their intended uses."

Hitachi S TEST Reagent Cartridge: Reported Device Performance

2. Sample Size Used for the Test Set and Data Provenance

The document describes test sets for various studies:

• Method Comparison (Internal):
  • TP: 115 clinical specimens
  • ALB: 118 clinical specimens
  • Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). Described as "clinical specimens."
• Matrices Comparison:
  • TP: 45 matched serum/plasma samples
  • ALB: 41 matched serum/plasma samples
  • Provenance: Not explicitly stated.
• External Site Precision Study:
  • TP: 3 "blinded serum samples" (low, middle, high) at each of 3 sites. Each sample assayed 30 times (6 times/day for 5 days). So, 3 samples * 30 replicates * 3 sites = 270 measurements per analyte for total precision.
  • ALB: 3 "blinded serum samples" (low, middle, high) at each of 3 sites. Each sample assayed 30 times (6 times/day for 5 days). So, 3 samples * 30 replicates * 3 sites = 270 measurements per analyte for total precision.
  • Provenance: "three external POL-type sites," implying clinical settings, likely within the US given the submission to the FDA. Retrospective/prospective not specified for the samples, but the testing itself was prospective within the study timeframe.
• External Method Comparison Studies (POL Accuracy Data Summary):
  • TP: Approximately 50-80 serum specimens per site (n=52, 52, 53). Total around 157.
  • ALB: Approximately 50-80 serum specimens per site (n=87, 81, 81). Total around 249.
  • Provenance: "three external POL-type sites," implying clinical settings, likely within the US. Retrospective/prospective not specified for samples but the comparative testing was prospective.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of those Experts

This document describes a diagnostic device for quantitative determination of Total Protein and Albumin. For such devices, "ground truth" is typically established by recognized reference methods, not by expert consensus (e.g., radiologists).

• Method Comparison (Internal and External): The comparison was made against a "standard laboratory system" or "comparative method as the reference method (x)." The specific details of this reference method are not given beyond its use for comparison. No information is provided about human expert involvement in establishing this ground truth.

4. Adjudication Method for the Test Set

Not applicable. Diagnostic devices like this establish their accuracy against a reference method, not through human adjudication of results.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done

No. This is an in-vitro diagnostic device that provides quantitative measurements. MRMC studies are relevant for imaging devices or those requiring human interpretation.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, all studies described (analytical sensitivity, linearity, precision, interference, method comparisons, matrices comparisons) represent the standalone performance of the device (Hitachi Clinical Analyzer E40 with S TEST Reagent Cartridges) in measuring TP and ALB concentrations in samples. These are automated processes without direct human interpretation of results for the purpose of the measurement itself. Human operators are involved in running the analyzer, but the "performance" here refers to the device's analytical capability.

7. The Type of Ground Truth Used

The ground truth for the performance studies was established using:

• Reference Methods/Standard Laboratory Systems: For method comparison studies, the device's results (Y) were compared to a "standard laboratory system" or "comparative method" (X). This is a common approach for establishing accuracy of new in-vitro diagnostic devices.
• CLSI Guidelines: Studies like Analytical Sensitivity, Linearity, and Precision followed CLSI (Clinical and Laboratory Standards Institute) guidelines (e.g., EP17-A, EP-6A, EP5-A2). These guidelines define how to determine these performance characteristics, often involving reference materials or established statistical methods for calculation rather than external ground truth.
• Defined Concentrations: For precision and interference studies, samples were used that represented specific (low, middle, high) or known concentrations of the analytes.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI. This is a traditional in-vitro diagnostic device based on chemical reactions and photometric measurements. Its "development" would involve optimizing reagents and calibration, not "training" an algorithm in the AI sense. Therefore, the concept of a training set as understood in AI/ML is not applicable here.

9. How the Ground Truth for the Training Set Was Established

As noted in #8, there is no "training set" in the context of AI/ML for this device. The ground truth for developing and calibrating such devices typically relies on:

• Primary Reference Materials: Highly characterized materials with known concentrations of analytes.
• Secondary Reference Materials: Materials traceable to primary reference materials.
• Validated Reference Methods: Established and highly accurate methods, often more complex or expensive, used to assign values to control or calibration materials.

The document implicitly refers to these as part of "assay performance claims were established on the HITACHI Clinical Analyzer."

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The S TEST Reagent Cartridge Alkaline Phosphatase (ALP) is intended for the quantitative measurement of alkaline phosphatase activity in serum, lithium heparinized plasma, or sodium citrate plasma using the HITACHI Clinical Analyzer. The S TEST Reagent Cartridge Alkaline Phosphatase (ALP) is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Measurements of alkaline phosphatase are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.

The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).

System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge ALP.

Chemistry reactions: Alkaline phosphatase (ALP) in the sample reacts with its substrate, pnitrophenyl phosphate (p-NPP), in ethylaminoethanol (EAE) buffer, to release p-nitrophenol (yellow). The ALP activity is determined by measuring the rate of p-nitrophenol production.

The provided text describes the performance characteristics and acceptance criteria for the Hitachi S TEST Reagent Cartridge Alkaline Phosphatase (ALP).

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" as a separate column for all metrics. However, the performance data provided implies that the reported results met the internal development criteria for each study. Where a specific acceptance range or threshold is mentioned (e.g., for interference testing), it is included.

2. Sample Size Used for the Test Set and Data Provenance:

• Analytical Sensitivity (Limits of Detection): Not specified, but likely involved multiple replicates for statistical analysis as per CLSI EP17-A.
• Linearity: Not specified, but involved samples spanning 5 U/L to 1,000 U/L as per CLSI EP-6A.
• 20-day In-house Precision: Three levels of samples, each tested in two runs, twice a day, for 20 days. This means 80 data points per level (2 runs/day * 2 times/run * 20 days). Total around 240 data points across 3 levels.
• Interference Testing: Two serum pools tested.
• Method Comparison (in-house): 97 clinical specimens. Data provenance: Not explicitly stated, but implied to be in-house or from a domestic source. Retrospective.
• Matrices Comparisons: 38 matched serum/plasma samples. Data provenance: Not explicitly stated, but implied to be in-house or from a domestic source. Retrospective.
• External Site Precision: Each site tested three blinded serum samples, six times per day for five days. This means 30 replicates per sample per site. With 3 sites and 3 samples, approximately 270 data points (30 * 3 * 3).
• External Site Method Comparison: Approximately 70 serum specimens per site, for a total of around 210 specimens (3 sites * ~70 samples/site). Data provenance: Not explicitly stated, but typically from within the country where the study is conducted (likely USA, given the FDA submission). Retrospective.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

This information is not applicable as the device is a quantitative chemical analyzer. The "ground truth" for the test sets (samples used in the studies) is established by the reference methods or known concentrations, not by expert interpretation.

4. Adjudication Method for the Test Set:

This information is not applicable as the device is a quantitative chemical analyzer. Ground truth is determined objectively through reference methods or known concentrations, not through expert adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance:

This information is not applicable. The device is a diagnostic instrument (chemistry analyzer) and not an AI-based imaging or diagnostic aid that involves human readers.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

The studies described (precision, linearity, method comparison, interference, matrices comparison) represent the standalone performance of the Hitachi Clinical Analyzer with the S TEST Reagent Cartridge ALP. This is the direct measurement by the instrument, without a human interpretation step.

7. The Type of Ground Truth Used:

The ground truth for the performance studies was established using:

• Reference Methods: For method comparison studies, the Hitachi system was compared against a "standard laboratory system" (predicate device or another established method).
• Known Concentrations/Values: For linearity, precision, and interference studies, samples with known or carefully characterized concentrations of ALP and potential interferents were used.
• CLSI Guidelines: Studies followed established Clinical and Laboratory Standards Institute (CLSI) guidelines (e.g., EP17-A for detection limit, EP-6A for linearity, EP5-A2 for precision, EP7-A2 for interference).

8. The Sample Size for the Training Set:

This information is not applicable. This device is a traditional chemical analyzer, not an AI/machine learning system that requires a "training set" in the computational sense. The device's parameters are set during its manufacturing and calibration process, not through a data-driven training phase.

9. How the Ground Truth for the Training Set Was Established:

This information is not applicable for the reason stated in point 8.

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