Minimally invasive total mesorectal excision is increasingly being used as an alternative to open surgery in the treatment of patients with rectal cancer. This systematic review aimed to compare the total, operative and hospitalization costs of open, laparoscopic, robot-assisted and transanal total mesorectal excision.This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA)  A litera12 studies were included, reporting on 2542 patients . Total costs of minimally invasive total mesorectal excision were higher compared to the open technique in the majority of included studies. For robot-assisted total mesorectal excision, higher operative costs and lower hospitalization costs were reported compared to the open and laparoscopic technique. A meta-analysis could not be performed due to low study quality and a high level of heterogeneity. Heterogeneity was caused by differences in the learning curve and statistical methods used.Literature regarding costs of total mesorectal excision techniques is limited in quality and number. Available evidence suggests minimally invasive techniques may be more expensive compared to open total mesorectal excision. High-quality economical evaluations, accounting for the learning curve, are needed to properly assess costs of the different techniques. Over the past decades, significant improvements in minimally invasive approaches led to the subsequent introduction of laparoscopic, robot-assisted and transanal colorectal procedures. Laparoscopic total mesorectal excision (L-TME), robot-assisted total mesorectal excision (R-TME) and transanal total mesorectal excision (TaTME) are now more widely used, especially after their safety and feasibility was established for the surgical treatment of extraperitoneal rectal carcinoma –9.A recently published multicenter randomized controlled trial by the REAL study group reported robotic surgery resulted in better oncological quality of resection and postoperative recovery than conventional laparoscopic surgery . SimilarSpiraling healthcare costs have led to an emphasis on value-based healthcare. Consequently, cost-effectiveness and ‘added’ value of new technologies such as minimally invasive TME must be compared to conventional techniques. It is suggested that R-TME has higher costs compared to L-TME due to increased implementation costs, costs of re-usables and longer operating times , 13. HowThis systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and in line with the protocol agreed by all authors . The stuThe study selection criteria were defined by applying the Population/Participants, Intervention, Comparison, Outcome, and Study design (PICOS) framework. Population: patients with rectal cancer undergoing TME. Interventions: open TME, L-TME, R-TME and TaTME. Comparisons: studies were deemed eligible independently of head-to-head comparisons . Outcomes: operative costs, defined as all surgical costs, including costs of the operating theatre, personnel costs, costs of disposables and costs for system purchase, maintenance, and updates. Hospitalization costs, defined as all non-surgical costs, including costs of hospital ward admission, therapy, prescribed drugs, laboratory tests, consumables, housing, and personnel costs. Total costs, defined as all surgical and non-surgical costs, in general these consisted of the sum of the operative costs and hospitalization costs. However, due to variation in cost components used per study as well as definitions used, costs were reported as described in individual studies and different reporting outcomes were evaluated for inclusion on a case-by-case basis. Notably, studies reporting total hospitalization costs generally referred to these costs as the combined costs of operative and hospitalization costs. RCTs, prospective studies and retrospective studies reporting from a prospective database were included. Excluded were studies that met at least one of the following criteria: (a) not published in English, French, German, or Spanish, (b) case reports, letters, conference abstracts, commentaries, and reviews, and (c) full text unavailable. In case of overlapping populations between studies, the study with the largest sample size and longest follow-up was included.st, 2000, until January 1st, 2023. Search syntaxes are provided in The systematic search was supported by an experienced librarian and performed for the period of January 1Four independent reviewers  extracted data of the included studies using a standardized data extraction form. Prior to data extraction training was provided for using the form. The tabulated data was used for evidence synthesis and quality assessment. Disagreements were solved through discussion, in which two additional authors were involved (MP and EC). The following data was extracted for all eligible studies: study characteristics , patient demographics , preoperative data  score), intraoperative data , postoperative data  stay, Clavien-Dindo classification of postoperative complications and mortality), and economic costs .To compare reported costs, all costs were converted from the date of publication to 2021 using the inflation of the country where the research was conducted. These costs were then converted to US dollars by taking the purchasing power parities into account  In case The quality of included studies was independently appraised by four reviewers  using the adjusted Consensus Health Economic Criteria (CHEC) tool  S4 and . The adjA narrative synthesis was performed to present the findings of the included studies following the European Social Research Council Guidance on the Conduct of Narrative Synthesis in Systematic Reviews . CategorAfter removal of duplicates, a total of 9780 citations were identified . FollowiFive studies compared L-TME vs. R-TME10,25,27,28,31), one L-TME vs. open TME , one L-T,27,28,31The mean CHEC tool score was 6.1 ± 1.6, which indicates a low methodological quality of the included studies. There were no studies of high quality (score of ≥12). Reasons for low score were mainly studies not being economic evaluations, inadequate study design for cost assessment and incomplete description of cost components.Eight studies compared costs of two or more techniques, 29, 30.One study   comparedOne study   comparedFive studies compared costs of L-TME and R-TME , 27, 30.One study   reportedFour studies reported costs of one technique , 31, 32.This systematic review aimed to provide an overview of the current literature regarding costs of open TME, L-TME, R-TME and TaTME, and reveals a lack of high-quality studies. A limited number of available studies suggest that total costs of the minimally invasive techniques are higher compared to their open counterpart. This may be explained by higher operative costs of the minimally invasive techniques. In terms of hospitalization costs, R-TME may be less expensive than L-TME. However, there was large heterogeneity between studies and available studies were at high risk of bias due to inadequacy in accounting for different cost components.Only two studies compared minimally invasive TME to open TME , 23. TheAdditionally, the hospitalization costs and operative costs of R-TME and TaTME may be higher compared to L-TME. Only one study compared TaTME with L-TME and reported significantly higher total costs of TaTME . No diffThe statements regarding potentially higher total costs of minimally invasive techniques compared to open TME should be interpreted with caution. Currently, high-quality evidence is lacking, with few comparative studies available, and large heterogeneity between studies. This is mainly caused by differences in the learning curve and statistical methods used. Firstly, heterogeneity due to differences in the learning curve among studies exists: while some studies report on early experience, others studies report on surgeons far beyond their learning curves. As differences between surgeons’ experience have previously been known to confound the assessment of minimally invasive TME outcomes , it coulSecondly, regarding heterogeneity among studies caused by the used statistical analyses, differences could be due to the cost components used to measure costs, the used statistical method and the used follow-up period. Regarding the cost components used to measure costs, the majority of studies only included in-hospital operative costs in the cost comparison. Hence, it was expected that minimally invasive techniques would be associated with higher operative costs compared to open surgery, as the instruments and console are significant cost items, while operative times are longer . HoweverS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 FileModified Consensus on Health Economic Criteria (CHEC) checklist tool. Questions used per category and explanatory note are provided.(PDF)Click here for additional data file.S5 FileNA, not applicable. The Consensus on Health Economic Criteria (CHEC) checklist is a current research standard for conducting systematic reviews which are based on economic evaluation studies and was used to rate study the quality of all studies included in this review. The results of the CHEC tool indicate risk of bias and applicability concerns. This study used a modified CHEC tool using categorical questions adjusted to study design of the included studies.(PDF)Click here for additional data file.S1 TableASA, American Society of Anesthesiology; BMI, body mass index; L-TME, laparoscopic total mesorectal excision; n, number of patients; O-TME, open total mesorectal excision; R-TME, robotic total mesorectal excision; TaTME, transanal total mesorectal excision; -, not available.(PDF)Click here for additional data file.S2 Tablea Other procedures include coloanal anastomosis, intersphincteric resection and Hartmann surgery.APR, abdominoperineal resection; CRM+, positive circumferential resection margin; L-TME, laparoscopic total mesorectal excision; LAR, low anterior resection; n, number of patients; NA, not applicable; O-TME, open total mesorectal excision; R-TME, robotic total mesorectal excision; TaTME, transanal total mesorectal excision; -, not available, * Data shows median values, (PDF)Click here for additional data file. 24 Apr 2023
 PONE-D-23-09962

 Economic analysis of open versus laparoscopic versus robot-assisted versus transanal total mesorectal excision in rectal cancer patients: a systematic review.

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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The study is well structured but there are some points to clarify:- In the section “laparoscopic versus open TME” Leung et al. reported significantly higher total costs of L-TME compared to open TME. Is there any information about specific fields such as hospitalization costs, post-discharge costs and indirect costs in current literature?- In the section “laparoscopic versus transanal TME” Candido et al. reported higher total costs of TaTME compared to L-TME and in details operative costs of TaTME were higher compared to L-TME, while hospitalization costs were comparable. Is there any information about specific fields such as instrumentation costs, conversion costs, post-discharge costs and indirect costs in current literature?Moreover evaluating the comparison between laparoscopic and transanal TME, why don’t you mention this paper?Vignali A, Elmore U, Milone M, Rosati R. Transanal total mesorectal excision (TaTME): current status and future perspectives. Updates Surg. 2019 Mar;71(1):29-37. doi: 10.1007/s13304-019-00630-7. Epub 2019 Feb 8. PMID: 30734896.- In the section “laparoscopic versus robot-assisted TME” it has been reported that “four studies showed significantly higher total costs of R-TME compared to L-TME while one study reported no significant differences. Two studies reported higher operative costs for R-TME while the hospitalization costs were lower for R-TME. Instrumentation costs were higher in R-TME than L-TME while conversion costs were lower in R-TME than L-TME. Lastly, costs of complications and ICU stay were significantly higher in R-TME than L-TME”.How do you explain the higher costs of complications and ICU stay in R-TME than L-TME? This topic should be enhanced.Moreover evaluating the comparison between laparoscopic and robot-assisted TME, why don’t you mention this paper?Milone M, Manigrasso M, Velotti N, Torino S, Vozza A, Sarnelli G, Aprea G, Maione F, Gennarelli N, Musella M, De Palma GD. Completeness of total mesorectum excision of laparoscopic versus robotic surgery: a review with a meta-analysis. Int J Colorectal Dis. 2019 Jun;34(6):983-991. doi: 10.1007/s00384-019-03307-0. Epub 2019 May 6. PMID: 31056732.- In the section “laparoscopic versus robotic versus open TME” Ramji et al. reported significantly higher total costs of R-TME compared to L-TME and open TME, operative costs were significantly higher in R-TME compared to L-TME and open. Is there any information about specific fields such as post-discharge costs and indirect costs in current literature?**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Reviewer #1: No**********https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  15 Jun 2023Professor Emily Chenette Editor-in-chief, PLoS OnePLoS One Editorial Office184 Cambridge Science ParkMilton, Cambridge CB4 0GAUnited Kingdom Groningen, the Netherlands. June 8th 2023Dear Professor Emily Chenette, editor-in chief of PLoS One,We would like to thank the reviewers for their review by providing comments and feedback, hereby enhancing the manuscript: “Economic analysis of open versus laparoscopic versus robot-assisted versus transanal total mesorectal excision in rectal cancer patients: a systematic review.” We would hereby like to send the revised manuscript for appraisal. We have taken all of the mentioned comments into account while optimizing and changing our manuscript. Enclosed you will find the revised manuscript. In yellow you will find the changes made in the manuscript as a reaction on the comments. In addition, below we provided an itemized, point-by-point response to the comments of the reviewers, including the page numbers of the revised manuscript. We hope that you might consider the adjusted manuscript for publication. Yours sincerely, On behalf of the whole study team, Ritchie T. J. Geitenbeek, MD, PhD-candidateUniversity Medical Center Groningen, Department of SurgeryMeander Medical Center, Department of Surgeryr.t.j.geitenbeek@umcg.nlE-mail:  General comments:Comment #1: - Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file namingWe have taken great care to make sure that our manuscript and files meet the PLOS ONE’s style requirements. We have made several modifications to our manuscript by using the PLOS ONE style template. We have added the following sentence, including the indicating symbol, on the Title page on lines 24 & 25: ^ Collaborators of the MIRECA  study group are listed in the Acknowledgments. We have changed the following words in the “Abstract” section on page 4, line 85 from: “Supplementary File 1” into: “S1 File”. We have changed the following words in the “Methods” section on page 8, line 168 from: “Supplementary File 2” into: “S2 File”. We have changed the following words in the “Data extraction” section on page 9, line 196 from: “Supplementary File 3” into: “S3 File”. We have changed the following words in the “Risk of bias and quality assessment” section on page 9, line 200 & 203 from: “Supplementary File 4 and 5” into: “S4 and S5 Files”. We have changed the following word in the “Study selection” section on page 10, line 224 from: “Fig. 1” into: “Fig 1”. We have changed the following word in the “Study selection” section on page 11, line 233 from: “Fig. 1” into: “Fig 1”. We have changed the following words in the “Study characteristics” section on page 11, line 243 from: “Supplementary Table 1 and 2” into: “S1 and S2 Tables”. Regarding the reference citations, we have changed all parenthesis into brackets throughout our manuscript. Furthermore, we changed our File naming to meet the PLOS ONE style requirements. Comment #2: - Thank you for stating the following financial disclosure: "This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors”. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”We have changed the following sentence in the “Funding statement” section on page 2, line 37 from: “This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.” into: “The authors received no specific funding for this work.”Comment #3: - Thank you for stating the following in the Competing Interests section: "EC is proctor for Intuitive Surgical and received a grant from this organization for the Vantage trial. No  support from this organization has been received for the submitted manuscript. Neither has there been any other activities or relations that could appear to have influenced the submitted work. All other authors declare: no support from any organization for the submitted work; no financial relationships with organizations that may have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. "Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”We have added the following statement to the “Competing interests” section on page 2, line 30 & 31: “This does not alter our adherence to the PLOS ONE policies on sharing data and materials.”Comment #4: - Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.After thoroughly reviewing our references, we have adjusted reference number 17, as this reference had not been correctly exported from our reference manager program. Subsequently, we have checked all references, ensuring that alle are complete and correct. We have not cited any retracted articles in our paper.Reviewer 1:Comment #1:- In the section “laparoscopic versus open TME” Leung et al. reported significantly higher total costs of L-TME compared to open TME. Is there any information about specific fields such as hospitalization costs, post-discharge costs and indirect costs in current literature?Thank you kindly for reviewing our manuscript and for providing this comment. We agree with the reviewer that insight into the specific fields  of the total costs would aid in discerning the cost difference between open TME and L-TME. Regrettably, the paper by Leung et al. does not focus primarily on the total costs of the two TME techniques. Besides the total costs of the techniques, no information on the cost components or any other relevant details contributing to the total costs are reported in the paper. Apart from our systematic review, we identified three additional articles that report on the total costs of open TME compared to minimally invasive TME that are mentioned in the “Discussion” section on page 17, paragraph 2. We agree with the reviewer that supplementing the article with further information regarding the cost components would benefit the readership of this article. Therefore, we have added the following sentence to the “Discussion” section, on page 17, paragraph 2, line 328, 329 & 330: “Within these studies, the higher total costs were attributed to elevated operative costs, which were only partially mitigated by lower hospitalization costs, resulting from a decrease in complications and length of hospital stay.” The articles did not contain any further information regarding post-discharge costs and indirect costs. Hence, we proposed for more high quality research that also include the indirect cost in their cost analysis in lines 446, 447 & 448. Also, we have changed the following sentence in the “Discussion” section on page 22, paragraph 1, line 446, 447 & 448. from: ”In addition, these comparative studies should be performed from a societal perspective and include indirect costs.” into: In addition, these comparative studies should be performed from a societal perspective and include indirect costs, particularly as these are not yet included in currently available evidence.”Comment #2:- In the section “laparoscopic versus transanal TME” Candido et al. reported higher total costs of TaTME compared to L-TME and in details operative costs of TaTME were higher compared to L-TME, while hospitalization costs were comparable. Is there any information about specific fields such as instrumentation costs, conversion costs, post-discharge costs and indirect costs in current literature? Moreover evaluating the comparison between laparoscopic and transanal TME, why don’t you mention this paper? Vignali A, Elmore U, Milone M, Rosati R. Transanal total mesorectal excision (TaTME): current status and future perspectives. Updates Surg. 2019 Mar;71(1):29-37. doi: 10.1007/s13304-019-00630-7. Epub 2019 Feb 8. PMID: 30734896.We sincerely appreciate this remark and the valuable additional literature. In response to the reviewers remark regarding specific cost field, we agree that insight into these components would add value to the comparison between L-TME and TaTME. However, despite reporting the inclusion of instrumentation into the total costs, the article did not provide the actual instrumentation costs in the article. No additional information on the cost components or any other relevant details contributing to the total costs were reported in the article, apart from those as provided in Table 2. Hence, we proposed for more high quality research that also include the indirect cost in their cost analysis in lines 446, 447 & 448. Also, we have changed the following sentence in the “Discussion” section on page 22, paragraph 1, line 446, 447 & 448 from: ”In addition, these comparative studies should be performed from a societal perspective and include indirect costs.” into: In addition, these comparative studies should be performed from a societal perspective and include indirect costs, particularly as these are not yet included in currently available evidence.” To our best knowledge, no other articles exist within the currently available literature that compare the costs of L-TME and TaTME head-to-head. Subsequently, there is a lack of evidence on the exact factors that lead to the reported costs difference between L-TME and TaTME that warrant further research. Furthermore, in the included article by Elbarmelgi et al., total costs of TaTME were reported. Though the article reported these costs were based on instrument costs, consumable costs and ward costs, the actual costs of these specific fields were not provided.Considering the additional reference as proposed by the review, we believe that the article provides an insightful overview on the present roll and future prospects of TaTME, and is of added value when evaluating the comparison between L-TME and TaTME in the discussion. Therefore, we have added the following sentence including the reference to the “Discussion” section on page 18, paragraph 1, line 345, 346, 347 & 348: “As reported by Vignali et al., currently available evidence suggests short-term (post)operative and oncologic results of TaTME are comparable to L-TME. However, analyses of the costs related to the procedure are required, in particular when a two-team operation is performed.Comment #3:- In the section “laparoscopic versus robot-assisted TME” it has been reported that “four studies showed significantly higher total costs of R-TME compared to L-TME while one study reported no significant differences. Two studies reported higher operative costs for R-TME while the hospitalization costs were lower for R-TME. Instrumentation costs were higher in R-TME than L-TME while conversion costs were lower in R-TME than L-TME. Lastly, costs of complications and ICU stay were significantly higher in R-TME than L-TME”.How do you explain the higher costs of complications and ICU stay in R-TME than L-TME? This topic should be enhanced.Moreover evaluating the comparison between laparoscopic and robot-assisted TME, why don’t you mention this paper?Milone M, Manigrasso M, Velotti N, Torino S, Vozza A, Sarnelli G, Aprea G, Maione F, Gennarelli N, Musella M, De Palma GD. Completeness of total mesorectum excision of laparoscopic versus robotic surgery: a review with a meta-analysis. Int J Colorectal Dis. 2019 Jun;34(6):983-991. doi: 10.1007/s00384-019-03307-0. Epub 2019 May 6. PMID: 31056732.The authors would again like to sincerely appreciate this remark and the valuable additional literature. In order to explain the higher costs of complications and ICU stay in R-TME than L-TME reported by Rouanet et al., we’ve added the following sentences to the “Discussion” section on page 18 line 360: “This may be explained as this study assessed patients receiving R-TME in 2015 performed by surgeons of which some may still have been in their respective robotic learning curve, which is associated with increased morbidity. Moreover, when assessing a cohort of patients receiving R-TME in 2018, after the robotic learning curve had been achieved and the team was familiar with the ERAS procedures involved, the authors reported that costs were reduced to a level that was comparable to L-TME, with lower costs in patients without co-morbidity. “ The effects of the learning curve on the hospitalization costs are further elaborated in the “Discussion” section on page 18, paragraph 2.Considering the additional reference as proposed by the review, we believe that the article provides an insightful overview on the comparison between R-TME and L-TME, that would add valuable information to our introduction. Therefore, we have the following sentence including the reference to the “Introduction” section on page 6, paragraph 2, line 115, 116 & 117: “Similarly, a systematic review and meta-analysis by Milone et al. reported R-TME was associated with significantly higher rates of complete TME resection, whereas L-TME had a higher incidence of nearly complete TME.”Comment #4:- In the section “laparoscopic versus robotic versus open TME” Ramji et al. reported significantly higher total costs of R-TME compared to L-TME and open TME, operative costs were significantly higher in R-TME compared to L-TME and open. Is there any information about specific fields such as post-discharge costs and indirect costs in current literature?We would to thank the review for his comment. As depicted in Table 2, the article by Ramji et al. provides information on a number of cost components, including ward costs, pharmacy costs, laboratory costs, PACU costs and imaging. Overall, the higher total operative costs of R-TME are attributed to the higher operative costs in this article. The article does not contain any information on post-discharge costs and indirect costs. Furthermore, to the best of our knowledge, no studies are currently available in literature that report on the post-discharge cost and indirect costs of open TME, L-TME or R-TME. Hence, we proposed for more high quality research that also include the indirect cost in their cost analysis in lines 446, 447 & 448. Also, we have changed the following sentence in the “Discussion” section on page 22, paragraph 1, line 446, 447 & 448 from: ”In addition, these comparative studies should be performed from a societal perspective and include indirect costs.” into: In addition, these comparative studies should be performed from a societal perspective and include indirect costs, particularly as these are not yet included in currently available evidence.”AttachmentResponse to Reviewers - PLoS One.docxSubmitted filename: Click here for additional data file. 11 Jul 2023Economic analysis of open versus laparoscopic versus robot-assisted versus transanal total mesorectal excision in rectal cancer patients: a systematic review.PONE-D-23-09962R1Dear Dr. Geitenbeek,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. 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We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an  It, therefore, plays a central role in facilitating motions of the upper body and extremity. Comparative studies across tetrapods indicate that anatomical variation in the pectoral girdle and proximal humerus plays a significant role in forelimb function by enabling or constraining range-of-motion (ROM) at the glenohumeral (GH) joint –4. PrimaAustralopithecus sediba, a species that possesses a mosaic of GH features that in turn resembles the orangutan (Pongo), chimpanzee (Pan) and gorilla (Gorilla) [A variety of traits and associated linear measures, ratios, and angles have been proposed to capture these inferred form-to-function relationships in primates. For example, traits possessed by species that engage in frequent overhead postures (e.g. hominoids)—a more globular humeral head with a large articular surface area ,8,9, a sGorilla) ? To addrGorilla) .in vivo (see below). Collecting accurate in vivo data using imaging technology such as biplanar videoradiography—which yields direct measurement of bone—is in some regards ideal but logistically challenging to capture, and moreover cannot isolate the direct contribution of skeletal morphology to ROM as it includes soft tissue constraints. A critical gap then lies in the link between how one captures relevant traits and derives related functional outcomes such as ROM in order to identify those measures that are more or less important in facilitating behaviour.Previous attempts to directly link anatomical traits and associated measures to primate GH mobility using functional assessments have provided significant insights into these questions, but also reveal limitations in their application. For example, measurements of ROM from dry bones are limited to independent rotations, successively sampling each degree of freedom  ,11. Rotain silico simulations to better account for complex joint interactions across all rotational degrees of freedom [In silico approaches that consider all 6 d.o.f. are well suited for investigating primate GH ROM given that GH translations are observed in vivo [More recently, paleontologists have turned to  freedom –18. This freedom ,19–23 or freedom ,25. Rece freedom ,26. In s in vivo ,28. Furt in vivo ; thus, m in vivo ). System in vivo . Models in vivo is based on its contributions to two established mechanisms. First, maximizing the available joint contact area reduces the compressive stress caused by the forces generated from external loading (e.g. weight bearing) and large muscle forces crossing the joint [Here, we extend a proximity-driven GH model  to simulhe joint . Second,he joint . In humahe joint . Considein silico simulation in a comparative framework. First, we use our proximity-driven GH model to quantify 3D ROM. We next combine existing and novel methods to quantify both ROM magnitude [A. sediba and compare these results directly to living primates.This study introduces a novel approach for quantifying 3D ROM in primates that incorporates both morphological analyses and agnitude  and ROM . 2 (a)Hylobates (n = 2), Symphalangus (n = 1) and Ateles (n = 1). The more general suspensory group included Pongo (n = 1) and Pygathrix (n = 1). The knuckle-walking group consisted of Pan (n = 3) and Gorilla (n = 2). The bipedal group consisted of modern humans (Homo sapiens) acquired from two previous studies  [Potto (n = 1) and Nycticebus (n = 1). Cebus (n = 1) comprised the arboreal quadruped group, and Macaca (n = 1) and Mandrillus (n = 1) comprised the terrestrial quadruped group. We included a dog  as a quadrupedal outgroup. The fossil A. sediba (n = 1) was not assigned an a priori locomotor group.We acquired scapula and proximal humerus bone meshes for species spanning phylogeny and diverse locomotor groups . The brachiator group included rial S2) ,33. Slowy) axis was aligned with the medial  border, the medial–lateral (x) axis was oriented perpendicular to the medial border and in the plane of the scapula blade and the anterior-posterior (z) axis was perpendicular to the blade of the scapula. The humerus coordinate system was defined based on proximal morphology, since the distal humerus was truncated in most CT scans. The cranial–caudal (y) axis was aligned with the long axis of the proximal shaft, and the location of the lesser tubercle relative to the centre of the humeral head defined the medial–lateral (x) and anterior–posterior axes (z).Several meshes were acquired directly from open-access databases , while met al. [Following the methodology of Marai et al. , we buil (b)joint spacing [fmincon function to optimize the humerus translations and included a nonlinear constraint preventing the scapula and humerus from interpenetrating. We considered poses to be within the ROM with a 5% proximity threshold . We chose a 5% threshold following a sensitivity analysis that found that altering the threshold from 2 to 8% had a marginal effect on the number of poses in the ROM and the resulting ROM metrics . To test our assumption regarding glenoid coverage and examine how predicted ROM compares with in vivo ROM, we compared our in silico ROM estimates with in vivo kinematics measured from biplanar videoradiography in 20 human participants .For each specimen, we simulated 197 173 rotational positions sampling the entire range of plane of elevation angle (−180° to 180°), abduction (0° to 180°) and axial rotation (−180° to 180°) at 5° increments. At each pose, the rotational position was fixed while the humerus was translated to minimize the difference between (i) the simulated joint proximity and (ii) a target joint proximity (see below), with the added constraint that the bones could not interpenetrate. The joint proximity is defined as the mean proximity between the glenoid vertices and humerus articular surface and is distinct from previous measures of  spacing  defined  (c)A. sediba).The proximity-driven ROM simulation required subject-specific estimates of target joint proximity. Given that the CT scans yield bone meshes that exclude cartilage, the joint proximity between bone meshes should—anatomically—represent the summed cartilage thickness of the humeral head and glenoid and any synovial fluid-filled space between the surfaces. Several cadaveric studies have reported a strong correlation between body mass and cartilage thickness in compressively loaded joints –39; howen = 17; see electronic supplementary material S4). Joint proximity was strongly correlated with humeral head radius across species  and, additionally, aligned with the intra-specific trend in joint proximity observed in the current human sample. For the ROM simulations, we calculated the humeral head sphere-fit radius for all subjects and set each subject's target joint proximity according to the scaling law.We, therefore, developed a custom scaling law that would require only dimensions from scapula and humerus meshes. For each subject with a CT scan acquired in an anatomical joint position, we calculated the joint proximity between the glenoid and humeral head articular surface . We thenWe performed a sensitivity analysis to determine how ROM metrics were affected by changes in joint proximity by varying joint proximity target values according to three physiologically plausible scaling laws . (d)To quantify the magnitude and location of ROM, we plotted rotational positions according to an adapted version of the spherical rotation coordinate system   is described by its abduction angle and plane of elevation angle. We analysed only the abduction level of the functional centre due to its association with locomotor and postural behaviours. Based on the defined scapula and humerus coordinate systems, this abduction level represents the inclination of the long axis of the humerus relative to the medial border of the scapula. Finally, we computed circumduction envelope—a measure of rotational freedom around the joint globe when axial rotation is freely enabled. We calculated the circumduction envelope as the area of an alpha shape encompassing the 2D point cloud of ROM poses projected onto the joint map with an alpha radius of 5. Given the small sample size of each locomotor group, we reported group differences in mobility, abduction level of the functional centre and circumduction envelope by visually comparing distributions rather than through statistical tests. We performed independent linear regressions among the three ROM metrics, performing an F-test for a non-zero slope. All statistical tests were performed at a 5% level of significance. To visualize differences in ROM metrics across primate phylogeny, we mapped ROM metrics onto a consensus tree generated from 10kTrees [phytools [ape [We calculated three metrics to summarize ROM . First, le space  . For subsequent morphological analyses (see below) and for applying insights to  (e)We tested the relationship between morphology and ROM on a subset of the sample including only hominoids, lorisids and arboreal monkeys. We excluded the terrestrial quadrupeds and the dog from morphological analyses to prevent them from driving trends. Given the large sample size of humans, we included only three representative individuals that possessed the minimum, median and maximum mobilities.F-test for a non-zero slope.We measured 12 discrete morphological parameters cited as having implications for GH ROM. Angles and linear measurements were calculated from landmarks manually identified in Landmark Editor 3.5 . Parameters relating to surface area were computed from areas isolated in Geomagic Wrap. Where appropriate, measures were scaled to scapula centroid size to ensure that shape factors affecting ROM were not skewed by differences in overall body size related to locomotor groups (i.e. large body size of African apes). Further details on the calculation and scaling of each parameter are given in the electronic supplementary material S9. We performed independent linear regression analyses of each ROM metric on each discrete measure, performing an  (f)x, y, z) were manually identified in Landmark Editor 3.5 . We applied 22 landmarks to the scapula [geomorph [Three-dimensional landmark coordinate data  or circumduction envelope , but mobility was strongly correlated with circumduction envelope .We computed all three ROM metrics—mobility, circumduction envelope and functional centre—for 40 individuals representing species spanning locomotor groups  and primComparing ROM metrics between distinct locomotor groups, brachiators had higher mobility and more highly abducted functional centres than terrestrial quadrupeds . CircumdAustralopithecus sediba had mobility consistent with the high-mobility groups  and a functional centre intermediate to modern humans and non-human apes. When comparing ROM metrics in the context of phylogenetic groups, non-human apes all possessed highly abducted functional centres but variable mobility relative to other primates  excluding terrestrial quadrupeds—identified features correlated with ROM measures. Because of their ability to discriminate between locomotor groups, we included only mobility and the abduction level of the functional centre in the morphological analyses. Morphological associations with circumduction envelope are reported in the electronic supplementary material S9. The discrete morphological analysis captured subsets of traits that predicted ROM  and explained 30.8% of the shape variation  and explained 9.6% of the variation . The first four principal components (PCs) accounted for 67% of the total shape variation. PC1 predicted the functional centre (. 4A. sediba. We found that mobility (the magnitude of ROM) and functional centre  are decoupled, meaning high mobility is not necessarily associated with abducted shoulder posture. Our findings suggest that non-human apes are not uniquely adapted for high 3D mobility but are perhaps adapted specifically for overhead ROM as all possess highly abducted functional centres. Morphological analyses revealed that functional centre was correlated with measures cited to be important for overhead behaviour, but mobility was less easily predicted from morphological features.In this study, we developed a proximity-driven model, and used it to predict the GH ROM of living primate species spanning a range of locomotor behaviours, identified associated shape-based traits and used our results to interpret the fossil hominin in vivo. For example, in humans, when the humerus is elevated 90°, joint proximity can be maintained for 360° of axial rotation—a motion restricted by ligaments and muscles in vivo. Any attempt to predict in vivo ROM would require GH soft-tissue properties that are impractical to estimate for all muscles and ligaments across all species and impossible in extinct taxa. We therefore did not intend for our model to replicate in vivo ROM perfectly. Comparing simulated ROM with in vivo ROM confirmed that, within humans, the proximity-driven model captures the general observation that the humeral head maintains coverage of the glenoid throughout ROM . However, the model does not perfectly replicate in vivo translations, and it indeed tends to overestimate in vivo ROM. Further testing is required to draw conclusions on the relationship between skeletal ROM and in vivo ROM in other primate species. Therefore, our model is more effective for comparing gross differences in skeletal ROM across locomotor groups. Although soft tissue properties will contribute to differences in mobility—and these properties probably vary across taxa—we assume that the bony morphology plays a prominent role in dictating the ROM within which the soft tissue provides further constraints.An important caveat to our bone-based model is that it is most appropriately applied in a comparative framework. We defined the ROM to include any position where the articular surfaces maintained proximity within a defined threshold . Indeed, some positions considered acceptable by our model would likely be prevented by soft tissue circumduction area previously measured in cadaveric experiments, with unexpectedly high circumduction ranges in quadrupeds and low circumduction ranges in brachiating hominoids [Hylobates and Ateles brachiate, we expect them to require freedom in axial rotation across the joint globe to easily set up their elbow and hand position for gripping substrates overhead [To evaluate the model, we tested whether our ROM metrics were consistent with expected differences in ROM of brachiators and terrestrial quadrupeds. Given their clear distinction in locomotor behaviour and morphology, we predicted brachiators would have higher GH mobility, larger circumduction envelopes and abducted functional centres relative to the quadrupeds. We also expected all primates to exhibit higher mobility, higher circumduction envelope and more abducted functional centres than the cursorial dog. We found that mobility and functional region captured the expected distinctions in ROM while circumduction envelope did not . Interesominoids . This dioverhead . As mobioverhead .Pongo, Pan and Gorilla all possessed relatively low mobility while retaining high functional centres. Although all are capable of overhead suspension, they generally move slower and more cautiously through the canopy compared with Hylobates and Ateles. They perhaps do not require high GH mobility as they can carefully adapt their posture or grip choice to move in a way that their ROM allows. Further, ROM profiles of Pan and Gorilla suggest that they have lower rotational freedom at lower abduction levels . This is perhaps due to their prominent humeral tubercles that presumably enhance the mechanical advantage of the rotator cuff muscles for stabilizing the GH joint during the stance-phase of knuckle walking [Gorilla also possessed lower mobility and functional centres than Pan . Within the context of the hominids, A. sediba possesses a functional centre that is intermediate to African apes and humans. This is consistent with its position on the predicted evolutionary trajectory from African apes towards humans in the scapula shape morphospace [A. sediba's high, human-like mobility may reflect a selection for complex tasks at low abduction levels requiring high axial mobility. This is consistent with adaptions at the A. sediba hand that are considered to have enabled tool use and precision grip while still enabling a strong grasp for climbing [Homo-like behaviour.While the phospace . This laclimbing ,59. At tclimbing ,60), yetOur morphological analyses suggest that morphological features associated with overhead behaviour are decoupled from features related to enhanced 3D mobility, despite previous assumptions that the two are integrated. For example, select features possessed by brachiating gibbons—a cranially oriented glenoid, a high inter-tuberosity angle and a small rounded glenoid—have been assumed to enable both high abduction levels and high overall joint mobility ,11,61. WA limitation of our study is that it was mainly conducted on open-access bone meshes, and thus we were limited to a small sample size for each non-human species. With our small sample, we observed high intra-specific variability in ROM metrics (particularly mobility) . Our senA. sediba suggests a dorsally located scapula and a pectoral girdle arrangement intermediate to Homo and Pan, further supporting a shoulder ROM intermediate to Homo and African apes [The GH ROM presented here does not account for differences in scapular position across species. Further modelling would be required to incorporate scapulothoracic configuration. Variation in where the scapula rests on the thorax alters how we interpret the anatomical meaning of the functional centre relative to the thorax. In hominoids, a long clavicle and a short scapular spine allow the scapula to sit on the dorsal side of the thorax, which orients the glenoid laterally ,66. Lorican apes .The scapular morphological characteristics we found here to be relevant for GH ROM could also implicate the scapulothoracic articulation. For example, the mediolateral breadth of the scapula is captured by PC1  and corrThe locomotor groups adopted in this study are intentionally broad, as our aim was to understand how summative ROM metrics varied across broad locomotor categories. Indeed, the various species categorized within each group differ in their frequency, technique and kinematics of locomotion. Exploring how these nuanced behaviours correspond with 3D ROM beyond summative metrics would be an interesting avenue of future study. Each individual's 3D ROM has a unique profile with complex 3D interactions, reflecting the extensive variability in ROM not currently captured in our metrics . Future studies focusing on a narrower taxonomic sample are well-suited for exploring the more nuanced variation in 3D ROM and locomotion.A. sediba. We found that enhanced GH mobility is neither unique to brachiators nor common to all hominoids. Rather, interpreting mobility and functional centre as different ‘functions’ enabled a clearer separation of locomotor groups. Further, two morphological analyses revealed that features strongly correlated with high abduction levels were independent of features correlated with mobility. These results suggest that high mobility and adaptation for frequent overhead behaviour are not necessarily coupled. This finding should be considered when evaluating competing hypotheses regarding the evolution of the hominoid upper limb. Considering the similarly high functional centres exhibited across non-human apes, we posit that the common locomotor and postural demand requires ROM spanning high abduction levels, but not high mobility. Kinematic analyses of extant primates engaging in locomotion in the wild, facilitated by recent advances in non-invasive motion capture technology, could provide further estimations of the GH ROM required for various locomotor styles and postures [In this study, we used ROM predictions to provide insight into the evolution of the hominoid shoulder and reconstruct the behaviour of the fossil hominin postures .In conclusion, these results offer a clearer picture of the relationship between GH morphology and ROM such that more informed predictions of ROM of fossil taxa can be made from morphometric analyses alone. Our results demonstrate that the complex interaction of articular features can alter ROM in ways not previously anticipated. Thus, proximity-based simulations, when applied in a comparative framework, can help illuminate function where isolated morphological analyses cannot. While our proximity-driven model was developed for the GH joint, it can be adapted to predict mobility at other joints such as the hip, elbow and knee. Prior to applying the model to other joints, researchers should carefully consider the suitability of proximity-driven translations and identify reasonable joint proximities to target in their ROM simulations. Extending this framework to other anatomical regions and fossil taxa will help to better understand key transformations in primate and hominin evolution.


The loss of phosphorus was relatively high the first year after bioreactor establishment with rates varying from 298.4 to 890.8 mg P m−3 d−1, but in the second year, the rates ranged from 12.2 to 77.2 mg P m−3 d−1. The investments and the costs of the bioreactors were larger than expected based on Danish standard investments. The cost efficiency analysis found the key issues to be the need for larger investments in the bioreactor itself combined with higher advisory costs. For the four woodchip bioreactors considered in the cost efficiency analysis, the N removal cost was around DKK 350 per kg N ($50 per kg N), which is ca. 50% higher than the standard costs defined by the Danish authorities. Based on the estimated costs of the four bioreactor facilities included in this analysis, a bioreactor is one of the most expensive nitrogen reduction measures compared to other mitigation tools.Nitrogen (N) and phosphorus (P) losses to surface and coastal waters are still critically high across Europe and globally. Measures to mitigate and reduce these losses are being implemented both at the cultivated land surface and at the edge-of-fields. Woodchip bioreactors represent a new alternative in Denmark for treating agricultural drainage water, and the present study—based on two years of data from five Danish field-based bioreactors—determined N removal rates varying from 1.49 to 5.37 g N mThe online version contains supplementary material available at 10.1007/s10661-023-11358-8. Nutrien3 woodchip bioreactors, Carstensen et al. (3) turned from acting as a phosphate source in the first year of operation to a phosphate sink in the second and third year.In a woodchip bioreactor, drainage water is routed horizontally or vertically through a basin filled with woodchips before it reaches an outlet  were built during the first half of 2018 and came into operation in autumn 2018, while Hofmansgave came into operation in January 2019. The facilities at Gyldenholm and Hofmansgave consisted of three bioreactors (i.e. 3 subunits) running in series, while the other facilities only had one bioreactor. The reason for constructing Gyldenholm and Hofmansgave with three bioreactors running in series was to lead water during periods of low flow to only one reactor to avoid complete reduction of NO3− and the reduction of sulphate with the risk of developing nuisance odour as hydrogen sulphide. Hence, with increasing water flow from the drainage catchment drainage, water would successively be led to basin two and three as well. The dimensions and design of each bioreactor are specified in Table This study includes results from five new bioreactor facilities located in Denmark Fig. . It was 3, reflecting differences in the drainage discharge from the catchment areas. The bioreactors were not dimensioned to receive all the drainage water from the catchment, and at high flow a fraction of the water was therefore bypassed by a manually set damper or pump at the inlet wells to prevent overloading of the bioreactor and thereby aiming at an HRT of minimum 10 h.The volume of the bioreactors varied from 271 to 652 mAll bioreactors except Hofmansgave were equipped with a bentonite geo-membrane  to prevent exchange of water between the surrounding soil matrix and the bioreactor. At Hofmansgave, the membrane was made of polypropylene  because the groundwater was saline. All bioreactors were filled with a layer of 1.2–1.8 m filter matrix consisting of 100% willow woodchips . This woodchip layer was defined as the active wet filter matrix of the bioreactors. Subsequently, the wet filter matrix layer was topped with an additional unsaturated woodchip layer of 0.3–0.5 m to allow methane oxidation .The five facilities were studied during two hydrological years (1 August 2018 to 31 July 2019 and 1 August 2019 to 31 July 2020), later referred to as the hydrological years 2018–2019 and 2019–2020, respectively. Although the mean air temperature in the two hydrological years was relatively similar, varying from 9.1 to 10 °C, the “annual” precipitation differed markedly, being 657–1135 mm in 2018–2019 and 569–859 mm in 2019–2020 Table .To measure the water flow, the bioreactors were equipped with electromagnetic flowmeters  connected to a data logger  that recorded mean flow velocity every 10 min. A flowmeter was placed at the outlet wells at all bioreactors, but at Hofmansgave and Gyldenholm, a flowmeter was also mounted at an inlet well placed upstream the distribution well, which controlled the amount of bypassing water. In this way, the total bypassed water and N could be calculated.3) is the water-saturated volume of the bioreactor, 3/T) where T is time integrated over the selected period, i.e. the whole period or just a day or an hour with flow. The water level was kept constant as the outlet pipes were fixed at a certain height, and since the hydraulic conductivity in woodchips is very high, only peak flow events might have resulted in a temporary, short increase (hours) of the water level. Porosity was assumed to be 60% based on studies by Bruun et al., (The hydraulic residence time (HRT) in the present study was calculated as et al., 2016b.3 of water at the main inlet and for every 240 m3 of water from each of the outlets from the three subunits. The ISCO samplers kept the sampled water refrigerated at 4 °C. At Egsmarken, Dundelum and Serupgård, the datalogger triggered the ISCO sampler  to take a sample for every 120 m3 of flow from the bioreactor. Samples were collected every second week and transported in an icebox to the laboratory. Upon arrival, the water samples were kept at 4 °C until analysis for TN and total phosphorus (TP). All TN samples were analysed using a Technicon AutoAnalyzer according to DS 3 of the filter matrix per year (g N m−3 yr−1) and per day (g N m−3 d−1). The latter was obtained when normalised with the number of days with flow  were taken automatically at all bioreactors by use of a CR1000 datalogger and ISCO water samplers  installed at the inlet and outlet. At Hofmansgave and Gyldenholm, the datalogger triggered the ISCO samplers to sample when the accumulated water flow reached 720 mThe purpose of the economic analyses was to estimate the required investment and the yearly costs of a bioreactor. Based on this and the effect of the bioreactors, the cost efficiency with respect to mainly N removal could be calculated and compared to other reduction measures  and US Dollar ($), where DKK 100 = $14.41 (exchange rate on 25.4.2022). The estimated lifetime of the investment was 20 years, and the discount rate used was 4% following the socioeconomic guidelines from the Danish Ministry of Finance  t−1  used in our cost analysis was 1.7 m due to the requirement of an unsaturated layer of 0.3–0.5 m woodchips on the top to promote methane oxidation. With time, the volume of the biomaterial will shrink, requiring addition of another 0.5 m layer of biomaterial roughly every 6 years . The average price of the biomaterial used was DKK 134 ($19) tThe running costs included additional biomaterial (woodchips), supposing addition of 0.5 m woodchips on top of the bioreactor every sixth year to compensate for loss of material , and it should be noted that the hydrological year 2018–2019 was relatively dry, which also impacted the TN load at the bioreactor inlets, except for Gyldenholm.In this and the following section, we present a synthesis of nutrient removal results. All the bioreactors removed TN during the study period, the average removal being 30.5% of the TN load (Table −3 d−1) to the bioreactors at increasing hydraulic load (and thus TN load)  was achieved at lower efficiency (percent TN). Thus, both the percent efficiency and the absolute TN removal should be considered when evaluating the annual, seasonal, and daily performance of different bioreactors.We hypothesised that the dry period had lowered the removal rates in 2018–2019 and, as expected, there was a clear increase in the TN load with an increasing hydraulic load to the bioreactors  was especially noticeable in the first months following bioreactor establishment, e.g. as shown for Serupgård Fig. . Overall−3 year−1 in their first year of operation. This is in line with the results of Carstensen et al. , resulting in a yearly cost of DKK 36,500 , which can be perceived as an additional, but perhaps not required, cost.Table The additional purchase of more biomaterial comes next. If a pump is needed, the costs increase as is the case for Gyldenholm where pump investment and electricity increase the costs, potentially also the consultancy costs.Table The P effect is negative in the first year and subsequently positive  than that in the Danish bioreactors (around 600 m2 in size).In a study by Christianson et al. , investmMoreover, costs related to replacement of biomaterial and advisory costs were not included in the analysis by White et al. . However2) and largest site (2500 m2)  to follow the requirements set by the Agricultural Agency. The advisory costs are much larger than expected, possibly related to the pilot nature of the project. Aarhus University had almost the same help from catchment officers that farmers might have received. Normally, farmers undertake project coordination themselves, but in our project, this was carried out by a consultant at a cost that the farmer might not be compensated for. This indicates that, in many projects, the consultancy costs may be higher than the amount included in the standard costs. This is also because the farmer does not want to bear the responsibility for the final acceptance of the project by the Agricultural Agency.The costs of comparable measures such as traditional wetlands are 34–39 DKK ($5–6) per kg N, and the costs of other agricultural measures like catch crops are 7–167 DKK ($1–24) per kg N and for set-a-side 24–96 DKK ($3–14) per kg N measured in the root zone. In comparisons with the effect of bioreactors, groundwater retention must be included. With a retention of 70%, this would increase the costs of e.g. catch crops to 23–556 DKK ($3–80) per kg N. When using a mix of cost efficient measures, the average costs of meeting the Danish WFD targets were estimated to approx. 80 DKK ($12) per kg N . So, the costs of the bioreactors are clearly higher than the average costs of measures in Denmark.−3 d−1, with an overall average of 2.90 g N m−3 d−1. The yearly N removal efficiency varied from 6 to 55%, with a mean of 30.5% across bioreactors and years. In the first year of operation, the bioreactors had a TP loss rate of 298.4 to 890.8 mg P m−3 d−1. However, in the second year, most bioreactors retained phosphorous at rates varying from 12.2 to 77.2 mg P m−3 d−1.The performance of five field-based bioreactor facilities, two bioreactors with three subunits, and three with a single bioreactor, was reported for two hydrological years. The TN removal rate varied from 1.49 to 5.37 g N mOverall, the annual costs of the four bioreactors in the present project were about twice the average costs compared to other nitrogen reduction measures  based on the actual size was, on average, ca. DKK 350 ($50) per kg N, which is around 50% higher than the standard costs used by the Danish authorities for bioreactor establishment. The cost efficiency linked to the P removal in year 2 showed large variations from around DKK 8000 to 73,000  per kg P for the four bioreactor facilities.Supplementary file1 (DOCX 4366 KB)Below is the link to the electronic supplementary material.


Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system.To evaluate (a) costs and medical resource use for chemotherapy-related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy.Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM=288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs  and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared.Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile  or febrile neutropenia  while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148  for patients with febrile neutropenia and $3,099  for patients with afebrile neutropenia (P less than 0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia  and 9.1% of total costs for patients with afebrile neutropenia . Mean


Background: The costs of transporting end-stage renal disease (ESRD) patients to dialysis centers are high and growing rapidly. Research has suggested that substantial cost savings could be achieved if medically appropriate transport was made available and covered by Medicare.Objectives: To estimate US dialysis transportation costs from a purchaser’s perspective, and to estimate cost savings that could be achieved if less expensive means of transport were utilized.Methods: Costs were estimated using an actuarial model. Travel distance estimates were calculated using GIS software from patient ZIP codes and dialysis facility addresses. Cost and utilization estimates were derived from fee schedules, government reports, transportation websites and peer-reviewed literature.Results: The estimated annual cost of dialysis transportation in the United States is $3.0 billion, half of which is for ambulances. Most other costs are due to transport via ambulettes, wheelchair vans and taxis. Approximately 5% of costs incurred are for private vehicle or public transportation use. If ambulance use dropped to 1% of trips from the current 5%, costs could be reduced by one-third.Conclusions: Decision-makers should consider policies to reduce ambulance use, while providing appropriate levels of care.


Chikungunya virus (CHIKV) is an infectious agent spread by mosquitos, that has engendered endemic or epidemic outbreaks of Chikungunya fever (CHIKF) in Africa, South-East Asia, America, and a few European countries. Like most tropical infections, CHIKV is frequently misdiagnosed, underreported, and underestimated; it primarily affects areas with limited resources, like developing nations. Due to its high transmission rate and lack of a preventive vaccine or effective treatments, this virus poses a serious threat to humanity. After a 32-year hiatus, CHIKV reemerged as the most significant epidemic ever reported, in India in 2006. Since then, CHIKV-related research was begun in India, and up to now, more than 800 peer-reviewed research papers have been published by Indian researchers and medical practitioners. This review gives an overview of the outbreak history and CHIKV-related research in India, to favor novel high-quality research works intending to promote effective treatment and preventive strategies, including vaccine development, against CHIKV infection. Aedes aegypti and Aedes albopictus mosquitos. The term ‘chikungunya’ is derived from the root word ‘kungunyala’ of the Kimakonde language, and alludes to the bending posture of patients infected with the virus [Chikungunya fever (CHIKF) is a virus-borne illness transmitted by mosquitoes that is brought on by an alphavirus from the Togaviridae family. This virus is classified as an enveloped virus with positive-stranded RNA, and the primary vectors are he virus . Like mohe virus . It has he virus . Infectihe virus ,5,6. Thehe virus .A. albopictus to disseminate the virus [A. albopictus is an endemic mosquito that is found practically everywhere, unlike A. aegypti, which is only prevalent in the tropics and subtropics [The very first report on CHIKV was from Tanzania, an eastern African country, in 1952 . Later, he virus . Becausebtropics . In 2005btropics ,27,28. Tbtropics . Argentibtropics ,35,36,37Climate change and shifts in vector and host populations may have increased CHIKV’s geographic expansion in addition to potential alterations enhancing viral fitness and transmissibility. Economic growth can’t shield nations from vector-borne illnesses; rather modern living may exacerbate an outbreak through travel, the aging of the population, and the accumulation of solid waste that can serve as a mosquito breeding ground. The United States armed force has acknowledged that CHIKV may be a biological weapon due to its biosafety level 3 (BSL3) pathogenicity. The National Institute of Allergy and Infectious Disease (NIAID) in the United States has designated it as a priority pathogen in category B, which ranks as biological agents’ second-highest category . The WHOEpidemiological evidence indicating that a single CHIKV infection gives lifetime immunity against all the current lineages raises the possibility that only one vaccination may be enough to guarantee lifetime immunity . TherefoErgo, this review focuses on the current status of biomedical research on CHIKV in the most populous country, India, and its epidemiology, clinical features, laboratory findings, management, and prevention adopting varied treatment strategies, with reference to the researchers and their affiliated institutions.The linear, positive-sense, single-stranded genome of the RNA alphavirus CHIKV is approximately 11.8 kb in size . It encoThe first CHIKV outbreak in India was recorded in the city of Kolkata in 1963, followed by Chennai, Puducherry, and Vellore in 1964 . RetrospThere have always been significant difficulties in the epidemiological surveillance of CHIKV infection, for instance, it can be challenging to distinguish CHIKF from other arbovirus-related ailments because of the similarities in their clinical symptoms or associated co-infections. Therefore, the severity of chikungunya is underestimated. Only precise serological and molecular assays measuring either the presence of anti-CHIKV antibodies in convalescent patients’ serum or the presence of CHIKV’s viral RNA can accurately diagnose CHIKF. To provide a more accurate assessment of incidence and prevalence, affected areas require more resources and surveillance. Nonetheless, there were only two virological testing laboratories in August 2006, the National Institute of Communicable Diseases (NICD) and the National Institute of Virology (NIV) for the entire country .Over the past few decades, CHIKV outbreak studies have become popular in India’s research field to study how it spreads and affects the various populations living in different climatic, cultural, and environmental conditions . A graphThe genomic and proteomic data of CHIKV are vast. The comparison of various CHIKV strain genomes and the study of their genomic and proteomic relations give a reasoned knowledge of genetic diversity and phylogenetic relationships of CHIKV. Sreekumar et al., sequenced the 11.7 kb entire genome of the virus and genetic variants from six different viral isolates  from three consecutive Chikungunya epidemics in Kerala were examined . ThroughA. albopictus human isolates resulted in the alteration of the A226V amino acid, as mentioned vide-supra [in-silico [Singh et al., reported that the ECSA genotype of CHIKV caused an epidemic between 2006–2010 and 2010–2014 in India ,75. Kumade-supra . Santhosde-supra . Later, de-supra ,82 and tde-supra . At the de-supra . Harsha de-supra . By usinde-supra . Whereasde-supra . Dutta ede-supra . They wen-silico ,90. Chaan-silico ,92.The amino acids from nsP2 1–95) and nsP1 (170–288) are responsible for their straight interaction with ATPase enzymes demonstrated through mutational analysis . The gen and nsP1Chaaithanya et al. investigated the role of chemokines and proinflammatory cytokines in CHIKV-induced chronic arthropathy and discovered that the main functions were played by the cytokines IFN-γ/β, IL-1, TNF-αl, MCP-1, IL-6, MIP-1β, and MIP-1α . Few unuA. aegypti cell line Aag2 that can control CHIKV replication, including miRNAs miR-100, miR-989, and miR-2b [Non-structural proteins nsP2 and nsP3 demonstrate RNA interference (RNAi) suppressor activity in the CHIKV proteins, according to research by Sunil’s team . Throughd miR-2b . The samd miR-2b ,104. Furd miR-2b ,106. In d miR-2b . Later, d miR-2b .in-silico method [A bioinformatics team led by Cherian from NIV examined the evolutionary rates and timeline comparability of CHIKV as inferred from the complete genome/E1 gene, paying particular attention to the early outbreaks (2005–2007) in the area bordering the Indian Ocean. The evolutionary timescale of CHIKV was calculated to be in the last 30 decades under a constant population relaxed clock model in bioinformatics . This teo method ,111,112.Sreekumar and colleagues were involved in proteomic analysis and viral replication studies by CHIKV infection, adopting in vivo and in vitro systems ,113. UpoThe lack of well-developed diagnostic techniques, licensed drugs, vaccines, and antiviral therapeutics led to the primary outbreaks of CHIKV in India. Usha’s group studied similarities between dengue and CHIKF and their co-infection  and theyBased on an examination of a variety of ocular symptoms in a cohort of CHIKV-infected individuals, conducted by Prajna, an ophthalmologist, the primary ocular symptom of the CHIKV infection included granulomatous and non-granulomatous anterior uveitis, retrobulbar neuritis, optic neuritis, and dendritic lesions . MahendrE.coli via cloning [in-vitro identification of the key molecules and pathways involved in CHIKV infection is made possible by the combined mRNA and miRNA signature by Saxena et al. [When Patil et al. assessed the level of CHIKV exposure by estimating the age-stratified prevalence of IgG antibodies ,147, Rav cloning . Adoptin cloning ,160,161.a et al. .A research team led by Parida from DRDE developed and analyzed the antigen capture ELISA for CHIKV early clinical diagnosis. Further, real-time RT-PCR assays for detection and quantification were also tested ,164. TheChloroquine is a popular anti-malarial drug with the potential for both prophylaxis and treatment of CHIKV . Parida’in-vitro and it can protect mice infected with the virus [According to Parashar et al., the administration of NS1 siRNAs and E2 can suppress CHIKV replication he virus . To creahe virus . Chattophe virus . When thhe virus . 17-AAG,he virus .Based on conformer and pharmacophore, Tomar and his team at the IITR discovered the peptidomimetic inhibitors of CHIKV-nsP2 protease. The molecular docking of the nsP3/4 junction peptide at the CHIKV nsP2 protease active site gave structural insight into the nsP3/4 peptide’s likely mode of binding and identified key molecular interactions for the substrate binding mode ,183,184.Chromolaena odorata as ayurvedic drugs to treat CHIKV infections. Homeopathic medicines like Eupatorium Perfoliatum Mother Tincture, Rhus tox, Influenzinum, Pyroginum, Arnica, Cedron, Belladonna, Ledumpal, Bryonia, and Nuxvomica are also used against CHKV [Vitex negundo, Hyptis suaveolens, and Decalepis hamiltonii are reported by Swaminathan [Vathasura kudineer, and the traditional Indian remedy Amukkara Choornam (Withania somnifera-based) exhibit antiviral properties against CHIKV [Cedrus deodara, Picrorhiza kurroa, Terminalia chebula, Ocimumtenui-florum, and Commiphora wightii plant extracts exhibited inhibition of CHIKV attachment via helicase and protease inhibition [in-silico drug screening method to find inhibitors of the CHIKV-nsP2 protease, a crucial non-structural protein needed for the reproduction of the CHIKV virus. The antibiotic novobiocin and the antihypertensive medication telmisartan were among the top hits on the screen and were found to be significant inhibitors of viral replication [Dilip et al. compared different medical ideologies  and investigated how conventional healthcare professionals treat CHIKV infections . In soutnst CHKV . The antminathan . Brahmanminathan . The ethst CHIKV ,200,201.hibition . This telication ,204.Due to the pressing need for vaccinations to protect against various viral illnesses, the Indian government launched the National Immunization Program, which resulted in the establishment of numerous authorized vaccine manufacturing facilities around the nation. Vaccine institutes were established at the beginning of the 20th century, and they gradually evolved in the direction of privatization, like BBIL. Besides BBIL, a few Indian agencies are fervently working on the CHIKV vaccine, including the Defense Research Development Establishment, the National Institute of Virology, and the Serum Institute of India.Pichia pastoris), chikungunya virus-like particles (CHIK-VLPs) were created by Parida’s team and tested as a potential vaccination candidate in Balb/c mice. Through the stimulation of TNF-α, IL-10, and significant quantities of IL-4, IL-2, and IFN-γ, a higher level of cellular immune response was seen, indicating a regulated response [An ILS researcher Chattopadhyay intended to comprehend anti-CHIKV CD8+ T cell response and epitope advancement-based immunotherapy for CHIKV infection, in silico . Polycloresponse . Furtherresponse .Sumathy from BBIL looked at evolutionary dynamics and serotype analyses ,219. BasA. aegypti mosquitoes in the maintenance and transmission of CHIKV to female mosquitoes was demonstrated by Mishra’s team at NIV. They verified that CHIKV can spread to female mosquitoes during mating by infected male mosquitoes. Infant Swiss albino mice became sick after being exposed to the body fluids of venomous female mosquitoes, demonstrating the infectiousness of the venomous virus [A. aegypti mosquitoes’ sensitivity to CHIKV. They established that mosquitoes perished at temperatures above 44.5 °C, which had an impact on the propagation of CHIKV [A. aegypti rosy eye mutants, they were able to determine the genetic basis of the virus’ vector competence for CHIKV [Ascogregarina culicis in the maintenance of CHIKV in vector mosquitoes was also examined by this group. They observed that the oocyst of the parasite in the A. aegypti mosquitoes directly transmits the CHIKV virus vertically. It has been hypothesized that A. culicis may play a significant part in CHIKV maintenance throughout the inter-epidemic period [A. aegypti, and carried out experimental CHIKV transmission via Anopheles stephensi mosquitoes [A. aegypti infected with CHIKV showed post-inoculation alterations in the enzyme activity of acetylcholinesterase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, and non-specific esterases [A. aegypti with DENV and CHIKV and the results proved that it multiplied effectively in the mosquitoes [Aedes mosquitoes’ ability to serve as CHIKV vectors [A. aegypti’s life table features and the pathways involved in egg-laying [The function of male us virus . Anotherof CHIKV . By emplor CHIKV . The sigc period . Yadav esquitoes ,227. Thesterases . The teasquitoes . Ravi frsquitoes . The patsquitoes . Desai l vectors . To ente vectors . Sunil eg-laying .Despite the earnest attempts and technological advancements, multiple concerns about CHIKV infection remain yet to be addressed. Point-of-care multiplex diagnostics to diagnose arboviruses are needed urgently, given the co-circulation of these viruses, including more specific serological assays for seroprevalence studies. More research and mitigation measures are required for the socioeconomic and environmental factors, that contribute to vector proliferation, particularly in low-income cities. Reasons behind the dramatic outbreaks in naive areas need to be unveiled. One of the economical and long-lasting approaches for reducing the disease is to combine therapies that are effective against several arboviral diseases. Lack of funding is a main crisis for the development of a successful CHIKV vaccine, although active immunization is the most economical preventative strategy. Therefore, there is an urgent need for global partnerships with industry, researchers, clinicians, public health officials, and other stakeholders in global health. These partnerships must include national and international, public, private, and government funding agencies to resolve this crisis. The quick deployment of SARS-CoV-2 vaccines in 2020 showed that the scientific community and financing organizations can overcome the customarily slow pace of vaccine development. Nonetheless, numerous potential vaccination candidates are currently undergoing clinical testing and will hopefully start the marketing authorization procedure soon. Yet, it is challenging to conduct vaccine efficacy studies due to the spontaneous emergence of CHIKV infections during outbreaks. An establishment of serological correlates of protection would be an appropriate strategy to make the marketing authorization simpler. The efficacy of the candidate vaccines is still unknown in the pediatric population because they are currently developed primarily for the adult population. Therefore, this part also needs to be considered.In India, CHIKV-related research has boomed during the last decades. According to our current data, the CHIKV-related research has concentrated on its varied aspects such as epidemiology, vector entomology, virology, clinical microbiology, cell biology, immunology, molecular biology, vaccinology, genetics, geo-medical and disease environmental studies, and disease burden estimation. Remarkably, hundreds of articles of high quality have been published by Indian researchers in peer-reviewed journals such as The Lancet, JAMA, Clinical Infectious Diseases, Journal of Medical Virology, Travel Medicine and Infectious Disease, Journal of Infection and Public Health, Virus Research and Scientific Reports. Following the resurgence of viral infectious diseases like Zika, Nipah, and the COVID-19 pandemic, there have been significant advances in surveillance, disease diagnostics like the CRISPR system, convalescent plasma therapy, and vaccine development like the mRNA vaccine. Nonetheless, as a priority pathogen of great concern due to its propensity to produce incapacitating illness, CHIKV is still regarded as a neglected tropical illness. The lack of funding, the unpredictable nature of the disease’s epidemiology, and the erratic interest in this pathogen, which has risen and fallen with the frequency of CHIKV outbreaks, have all hindered the development of CHIKV research progress. The loss of lives during the latest COVID-19 epidemic and the 1918 Spanish flu pandemic emphasizes the usefulness of vaccines in containing epidemics. Albeit a wide range of potential preclinical and clinical vaccine candidates have been developed in recent years, and it can be considered a milestone in the fight against this debilitating disease, there are presently no approved medicines or vaccines to prevent CHIKV infections. Ergo, this review briefs the CHIKV research in India and put forward the priorities and suggestions to favor a positive outcome. Hitherto, it is alluring to conjecture that in par with the world’s hastening CHIKV research, and heightened necessity for research and development of efficient medication and/or vaccine for this neglected tropical illness, Indian scientists will be able to contribute adequately and the cure will be available sooner than we anticipate.