Intra-Articular Hybrid Hyaluronic Acid Injection Treatment in Overweight Patients with Knee Osteoarthritis: A Single-Center, Open-Label, Prospective Study

Round 1

Reviewer 1 Report

Comments to the Authors

The manuscript (applsci-1308277) entitled “Intra-articular hybrid hyaluronic acid injection treatment in knee osteoarthritis in overweight individuals: a single-center, open-label, prospective trial”, describes the pain relief and disability reduction efficacy of the ultrasound-guided intra-articular injections of a hybrid hyaluronic acid complex (Synovial H-L) for the treatment of knee osteoarthritis (OA) in overweight patients. The authors concluded that intra-articular infiltrative treatment of Synovial H-L improved OA-related disease severity, cardiopulmonary function, and analgesic intake. The findings are interesting and the manuscript’s flow is logical. In my opinion, the manuscript can be accepted after minor revision.

Minor comments:

1. There are many incorrect spaces between words in the entire manuscript. It needs to be corrected.

Example) line 2: ‘acidinjetion’, line 3: ‘inkee’, line 24: ‘albeit modifiable,risk’, line 73: ‘drugstill’, and many others.        

2. Although the authors described that pain was evaluated through the Numeric Pain Rating Scale (NRS) in the Method and Results section, the data in Table 1 and Figure 1 shown in the Visual Analog Scale (VAS). What grading scale was actually used in the study?
3. Separate annotations should be provided so that readers can easily understand the data shown in Tables 1, 2, and Figure 1.
4. Line 181, ‘… a mean of 8 at T1…’ should be corrected as ‘… a mean of 8 at T0…’
5. The entire manuscript needs to be checked and corrected for typos. Eg. Line 90, ‘Sinovial H-L’ should be corrected as ‘Synovial H-L’
6. Please indicate the detailed information of the Synovial H-L provider/manufacturer (name, city, state, country)

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Minor modifications:

line 48, structural is used for structural evolution in KL, for tissues the terms is not adapted.

Spaces between words are missing, this affects the clarity of the text : line 58,85, 124... and abstract, 

line 13: your work is on knee, why do you use refeences on hip ? they are enough studies on knee: please change.

line 88: to stimulate fibroblast metabolism, in vitro ? to specify

line 72 : Is the use of proton pump inhibitors systematically recommended with NSAIDS ? justify or remove.

line 116: why authors excluded stade 3, clasically only stade 4 were excluded. because we know that HA works less well on the severe stages. 

line 123: precise when is T1 ? "end of the treatment" is not informative.

description of the population must be moved in results part (line 125-126), idem line 149-150

line 137 to 145: please to simplify and reduce this chapter.

The material and method section should be revised, simplified and better structured. the endpoint must be specify !T1 is at 1 month, 3 months or 6 months ? or when the authors decided ? outcomes have to be specify : pain in last 48 hours ?, Womac global or Womac pain ?

please to change "P" by "p" in statistical chapter

in different tables and results chapter, please to specify when you use standard deviation (SD), this must be defined, we don't know what the numbers in brackets correspond to. legends in table 1 are lacking.

Please to add legend in table 2, specify means , n, SD ....

there is no limitation part of the study, no discussion of the absence of a comparator group or of the number of subjects. it is difficult to conclude on an effectiveness considering these points especially since at the end of the manuscript we still don't know what was the delay between T0 and T1 without forgetting the notion of lost of sight?

 

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

Overall I think that this article is an interesting study and has a lot of potential but a few things require improvement.

The English language needs moderate change - only a few minor mistakes that I refer to in the next paragraph.

In the Abstract section (Lines 24-27) please pay attention to word spacing e.g. „patientsin terms ofdisease” or kneeOA. There are similar mistakes in the whole manuscript though so it needs to be thoroughly read and corrected. 

In Materials and Methods (Lines 117-118) there’s a repeat of a word „previous” - we kindly ask to avoid repetitions and change one of these words in order to do so. 

VAS pain scale is simple and acceptable method to check the effectiveness of treatment, why did not you use it? NRS is a better one, why?

There is no mention about the general status health of the patients and if they used any medications. Some systemic disorders and specific drugs can distort the results. Pleases relate.

Exclusion criteria must be detailed.

References must be renewed: 2021 – only 1 paper, 2020 – only 1 paper, 2019 – only 1 paper, the rest are older.

The authors paid no attention to the bibliography formatting methodology required by the journal, so, it is not compatible with the authors' guidelines.

Did patients underwent any diagnostic or therapeutic procedures before or between the HA injections or maybe took analgesics during the injections? It not mentioned in the text, and it could influence on results, due to synergism.

It would be a good addition to the text if the authors explained in more detail the difference between overweight and obese patients providing data for both (such as BMI spectrum and overall % of overweight and obese people in Italian and/or worldwide population separate for men and women). Was there a statistically significant difference between the effectiveness of treatment of OA in overweight and obese patients? 

It is a shame that the observation period is only around 6 months. If possible - it would be beneficial for the manuscript to provide (if not from the authors’ own research and observations then from other scientific papers discussing this subject) the long-term results of the proposed treatment. Also - what is the expected prognosis for patients if left untreated and after what period of time they might need to repeat this procedure? 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The quality of study is poor

Author Response

REVIEW 2

1) Thanks. As recommended, we have expanded the part of the introduction on conservative treatment and added the recommended bibliography.

2) Thanks for the advice. We have modified and improved the discussion.

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors have not corrected the grammar and spacing between words despite claiming to do so - please address my remarks with care. The spacing mistake exist also in some parts of the newly added text e.g. Line 244 “HAviscosuplementation” is written with no space bar. 

I understand and agree that forming two completely separate groups of patients (obese and overweight) in this case is not needed although I still believe that adding this just as an information to the manuscript would be beneficial to the overall text as well as adding a small paragraph with the BMI ranges for all those groups and statistics that I asked for in my first review. 

Regarding my last remark - I think that adding only one sentence and one study concerning the long-term results is not enough and also the study is very vague on the subject. I understand that the study group was very small but this doesn’t relieve the authors from the obligation of providing more evidence-based study results citing other authors. There should be at least a comparison of a few papers touching on this subject showing the difference or similarly of results that all the authors have in common and how it applies to this manuscript. 

Also, there are mistakes in the literature section still, e.g. in 19 and 20 all authors should be included instead of „et al”, there are typos, incorrect spacing and the publication year is in the wrong section.

Overall, I think that the article needs either extensive revision or it should be rejected as it cannot be accepted for publishing in the current form. 

Author Response

REVIEW 3

1) Thanks for the observation. We apologize and have corrected the grammar and word spacing.

2) Dearest reviewer, we are sorry for this misunderstanding. We enclose the statistical evaluation of the two groups below:

“To assess the difference in the two groups, we considered the change in WOMAC, SF-12, and VAS values between T1 and T0: in this way, we measure how much the values have changed after treatment. We then performed tests to see if there is a significant difference between the two groups. Here are the results. As expected, the tests were not significant because of the low numbers of overweight subjects. The number of subjects in the sample is 37. Of these, at T0, 31 are obese, and 6 are overweight. Because of the strong unbalance of the subjects in the two modalities, carrying out any test is not very useful due to the low information available: the standard errors obtained are very high in the overweight group; consequently, the tests do not admit significant differences unless there is a very high diversity between the groups.”

	mean in group Obese	mean in group Overweight	t-test	p-value
VAS	-2,87	-3	0,21	0.839
SF-12	2,74	3,5	-0,27	0.792
Womac	-32,3	-31,7	-0,09	0.927

 

We ask you to decide whether or not to include these data in the work.

3) Thanks for the observation. We have modified the discussion by adding to line 286 some similar studies on the long-term effects of hyaluronic acid in osteoarthritis of the knee.

4) Thanks for the observation. We have corrected the bibliography based on the guidelines of the journal.

Author Response File: Author Response.docx

Round 3

Reviewer 3 Report

I recognize that the authors have indeed taken my remarks into consideration and implemented all of the suggested changes into the manuscript which I am glad to see. I think that at this point and in the current form the text is suitable for publication and I can finally give it my full approval. 

Author Response

Thanks for the comment

Author Response File: Author Response.pdf