Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is well written and organized. It is scientifically sound and has importance to solve the problem of AKI, although there are some issues that should be taken in consideration:

1- It is advised to use 4-6 keywords, authors used more.

2- The abbreviation is defined when it is mentioned first time. AKI is defined in line 25 and 48. Please double check the whole paper according this issue.

3- In lines (168-169) authors reported that optical sensors positioned at predetermined volumetric thresholds, please clarify this issue more in the text.

4- In lines (267-268) the abbreviation comes before the definition, correct this please.

5- In lines (310-319) it is not clear to the reader how the final output accurately reflected the transferred volume, it is advised to give more explanation and prove.

6- The legends of some figures is too long (figure 5) and they repeat the explanation in the text. Please double check this issue for all figures.

7- As authors mentioned in line 464, the sample size of the studies for V3 is very limited. How this issue could affect the analysis of the results? 

8- More recently published journal articles should be cited. 

 

Author Response

Please see the attachment. Thank you. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript describes the iterative design and validation of an automated urinometer ("P-meter") based on non-invasive optical sensors, a peristaltic pump, and microcontroller control. They present three prototypes (V1, V2, V3) evaluated in animal studies (285 h total) and compare volumes measured with gravimetric reference corrected by specific gravity of urine. They report for V3 a regression slope of ~0.99, R² ≈ 0.988, mean bias ≈ −0.10 mL and ~94% within agreement limits; V1 and V2 show larger biases and different R². The study argues clinical potential for the early detection of oliguria/AKI and discusses feasibility of manufacturing and deployment.  

 

Relevance and novelty. Accurate real-time urinary volume automation is clinically meaningful (ICU, surgery) and volumetric integration (Q×t) approach with external optical sensors and disposable fluid line is attractive for cost and sterility. The manuscript is well-motivated and frames the problem versus commercial/experimental solutions. 

Global balance. Although promising, the article presents quantitative inconsistencies, methodological gaps (especially in flow/flow validation and statistical analysis), and elements of reproducibility and editorial compliance (data, supplements, figures/tables) that require substantive correction before a positive decision. 

Top Comments 

Consistency of results and assertions 

• R² and "superiority" of V3. In the abstract it is stated that V3 "outperforms" V1/V2, but the reported R² are lower for V3 (0.9889) compared to V1 (0.9971) and V2 (0.9941). If the criterion of superiority is bias or slope close to unity, it must be made explicit and nuanced ("improvement in bias and slope, at the expense of R²"). I suggest rewriting all comparisons with a composite metric (e.g., RMSE, MAE, slope, intercept, LOA), avoiding conclusions based on a single metric.  

• Internal divergences. In V1/V2, ≈ 0.9998 (V1) and 0.9995 (V2) are declared R² after calibration, but subsequent validations include R² = 0.9971 (V1) and 0.9613 (V2). Clarify whether the first R² correspond to bench calibration and the second to independent validation; In this case, explicitly label the sets and describe the partitioning procedure (train/validation).  

• Percentage within LOA. The text indicates 94.20% within the limits for V1, but Table 1 indicates 93.72%; harmonize figures (text, table and figures). Ditto for V3 (94.19% in text, 94.18% in table).  

Flow rate validation, not just volume 

The device declares real-time flow monitoring, but validation focuses on volume per interval. Missing: 

• Flow calculation method (time window, smoothing, Q×t derivation per cycle, and aggregation). 

• Flow error metrics (RMSE, bias, response to discontinuous flows due to ureteral peristalsis, artifacts due to airlocks). 
  I request to include a bench protocol with standard perfuser/pump and variable flow profiles (step, ramp, pulsatile), with metrological traceability, and to report accuracy and dynamic response of the flow.  

Sample size and generalization 

V3 validation is limited to n = 86 measurements/5 experiments/30 h, exclusively in anesthetized animals. I require: 

• Extended hours and experiments (e.g., ≥300–500 h for V3) with variability of conditions (viscosity/USG, red blood cells, turbidity). 

• A potency analysis to account for and detect clinically relevant effects (e.g., relative error <1–2%). 

• Although I don't require clinical trials now, they include a clinical transition plan (criteria, endpoints, interferers).  

Calibration and linear correction: transparency and replicability 

The use of two linear equations y = m x + c according to threshold/sensor is mentioned, but the exact values (m, c) and uncertainties are not provided. Include: 

• Equations and coefficients per prototype (with 95% CI). 

• Validity range and criteria for change between equations (sub-threshold/supra-threshold). 

• Residual and heteroskedasticity analysis (e.g., Breusch–Pagan test). 
  In addition, the use of USG to convert mass to volume is suitable; include refractometer uncertainty and error propagation in the final calculation.  

Comparisons with commercial systems 

The text compares to ClarityRMS, Urinfo 2000/FlowSense, Accuryn, and others, but with heterogeneous metrics (bias, %error, different endpoints). I propose: 

• A standardized comparison table (same range of volumes/flows, same metrics: bias, RMSE, LOA, cost per patient/day, installation requirements). 

• Head-to-head bench test with at least one available commercial system (e.g., simultaneous comparison of volumes/flow rates in a test circuit).  

Data and code availability 

The Data Availability Statement is listed as "N/A", which does not comply with editorial policy and limits reproducibility. I request: 

• Raw data repository (time series, timestamps, reference volumes, USG). 

• V3 firmware (microcontroller), analysis scripts, and CAD/STL files (disposable components and assemblies), plus bill of materials (BOM). 
  Provide repository (Zenodo, OSF, GitHub) with DOI and license.  

Safety, sterility and risks 

A non-contact architecture and disposable fluid line with hydrophobic filter is described; very suitable. Missing: 

• Validations of compatibility with pathological urine (hematuria, pyuria, crystals) and their impact on optical detection. 

• Fault management plan (sensor/pump error → overflow): add FMEA, alarm, and recovery times. 

• Evaluation of cleanliness and bioburden in reusable components (optical drive) and use cycles.  

Statistical treatment 

Report numerical LOAs (mean ±1.96· SD) for each prototype and by volume ranges; Include residual plots and, given the repeated nature of measurements

 per experiment, consider linear mixed models (random effect per animal/experiment) to avoid inflating n and control intra-subject correlation.  

Figures, tables and supplements 

• Figure 1–5: Improve readability (axis units, line weight, font size). 
• Table 1: Correct numerical inconsistencies (see §3.1) and define "95% CI" exactly (% of measurements within LOA?). 
• Supplement: the link is placeholder (mdpi.com/article/doi/s1). Number correctly (Fig. S2–S5; "Figure S:" appears without a number for the EZO-PMP) and provide actual files.  

Regulatory and clinical integration track record 

Design improvements and an expansion plan are mentioned; Add a short section on: 

• Intended regulatory classification (EU/US), biocompatibility testing (ISO 10993 applicable to parts in contact with fluids if any), electromedical/electrical safety if applicable, and integration with HL7/EMR.  

 

Minor Comments 

• Terminology: use "microcontroller"/"embedded controller" consistently; in V3 PIC32 is cited after extensively describing Arduino Mega; clarify in a V1→V3 changetable (CPU, pump, chamber, filter, housing).  
• References: incorporate DOIs where they exist; standardize "Available online" and access dates; See §4 (many product entries and patents).  
• Units and symbols: standardize mL/min, mL/h, symbols in text and axes; avoid "≈" in key quantitative results (substitute for values with 95% CI).  
• Writing: review small typos ("interception" → "intercept", "euvolemic" → define clinical context; consistency of percentages and figures throughout the manuscript).  
• Ethics and funding: the IACUC is correctly indicated; Add material availability statement (pumps/sensors with part number).  

 

Conclusion and recommendation 

The work deserves consideration for its technical contribution and potential clinical application. However, in order to sustain the assertions and guarantee rigor and reproducibility, major corrections in results, methodology, statistics, and complementary materials are necessary. 

Recommendation: Major review with re-evaluation after incorporating the proposed changes. 

 

List of required actions (checklist for authors) 

1. Restructure V1–V3 Benchmarks: Define primary/composite metrics (bias, RMSE, slope, LOA) and align text, figures, and table.  
2. Provide flow validation (controlled bench test + accuracy/dynamic response metrics).  
3. Calibration transparency: publish equations (m, c, 95% IC), ranges, and residuals; include uncertainty propagation (USG, balance, refractometer).  
4. Expand V3: hours/experiments and power analysis; Describe a preliminary clinical plan.  
5. Data and code: public repository with DOI (raw data, firmware, scripts, CAD/STL, BOM). Update Data Availability.  
6. Advanced statistics: numerical LOAs, mixed models by repeated measures, analysis by volume/flow ranges.  
7. Safety: pathological urine tests, FMEA, alarms, use/cleaning cycles; Clarify disposable/reusable components.  
8. Figures/Table/Supplement: correct numbering and discrepancies; improve readability; upload actual supplementary materials.  
9. References: add DOIs, standardize style; Verify accuracy of quoted figures from trading systems.  
10. Regulatory/IT Path: Brief Plan (Classification, Standards, EMR/HL7 Integration).

Author Response

Please see the attachment. Thank you. 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

After reviewing the revised version of the manuscript, I believe that the work presents substantial advances in consistency and methodological clarity, and addresses a relevant clinical problem with an innovative solution. However, critical limitations remain in terms of reproducibility and transparency, especially regarding the availability of data and materials.

Recommendation: The article may be considered for publication only if the authors comply with the requirements for openness of data and materials, in line with editorial policies and good scientific practice.

I request that the editor require the authors to provide:

 

A public repository (Zenodo, OSF, GitHub, or other equivalent) that includes:

 

Raw data: time series, reference volumes, specific gravity measurements.

V3 prototype firmware (microcontroller).

Analysis scripts used to process data and generate figures/tables.

CAD/STL files of disposable components and assemblies.

Bill of materials (BOM) with references to key parts.

 

 

The repository must have a DOI and open licence, ensuring traceability and reuse.

 

These actions are essential to ensure reproducibility, enable independent verification, and comply with the transparency standards required by the scientific community.

Conclusion: I recommend publication conditional upon delivery of the complete repository prior to final acceptance.

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf