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Statistical analysis | Statistical analysis was performed using IBM SPSS Statistics 25.0.0.2 (IBM, Armonk, NY, USA). Patient data were analyzed with the Chi-Square and the Kruskal-Wallis test. According to McAlinden et al [ | PMC9847907 |
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Results | PMC9847907 |
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Short term analysis | In total 30 patients with DED were screened. 20 patients fulfilled the inclusion criteria, had no exclusion criteria, and were randomized to receive one of the two study medications (CN-group: n = 10; 5 males; 5 females; mean age = 40.8 ± 16.9 years; F6H8-group: n = 10; 3 males; 7 females; mean age = 39.2 ± 18.5 years). 10 of the 20 patients were randomly selected whose second eye served as a control group (control: n = 10; 6 males; 4 females; mean age 41.2 ± 19.0). There were no significant differences gender (X | PMC9847907 |
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Gender distribution (short term analysis group). | The gender distribution was calculated using the chi-square test.CN = cationic nanoemulsion of mineral oil; F6H8 = Perfluorohexyloctane. | PMC9847907 |
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Lipid layer thickness (in ICU) at baseline and consecutive measurements. | The measurement values up to 120 min after application were compared with the baseline using the Wilcoxon test. All p-values were adjusted for 3 comparisons according to the Bonferroni method. An asterisk with the corresponding p-value indicates a significant change compared to baseline measurement. ICU = Interferometric Colour Units; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.At baseline, there was no difference of RMS values between the three groups (H (2) = 1.2; p = 0.5). Immediately after application, CN increased RMS (z = -2.6; p = 0.027) from 0.42 ± 0.06 μm to 0.48 ± 0.08 μm ( | PMC9847907 |
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RMS values (in μm) at baseline and consecutive measurements. | The measurement values up to 120 min after application were compared with the baseline using the Wilcoxon test. All p-values were adjusted for 3 comparisons according to the Bonferroni method. An asterisk with the corresponding p-value indicates a significant change compared to the baseline. RMS = Root Mean Square; μm = micrometer; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.There were no harms observed in either group. | PMC9847907 |
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Long term analysis | In total 59 patients with DED were screened. 42 patients qualified for study inclusion, five of which were lost to follow-up or were excluded for using other tear supplements ( | PMC9847907 |
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Lipid layer thickness (in ICU) at consecutive measurements. | perfluorohexyloctane | The LLT at 4 and 12 weeks were compared to the LLTat baseline using the Wilcoxon test. All p-values were adjusted for 2 comparisons according to the Bonferroni method. An asterisk with the corresponding p-value indicates a significant change compared to the baseline. ICU = Interferometric Colour Units; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.Higher order aberrations as measured by the RMS values did not differ at baseline (H (3) = 3.0; p = 0.4) between the three groups. Neither the application of CN (X2 (2) = 0.7; p = 0.7) nor of F6H8 (X2 (2) = 1.0; p = 0.6) lead to a change in the RMS values within a 12-week observation period ( | PMC9847907 |
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RMS values (in μm) at baseline and consecutive measurements. | The RMS values at 4 and 12 weeks were compared with the values of the baseline using the Wilcoxon test. All p-values were adjusted for 2 comparisons according to the Bonferroni method. An asterisk with the corresponding p-value indicates a significant change compared to the baseline. RMS = Root Mean Square; μm = micrometer; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.At baseline the NIBUT between the three groups did not differ significantly (H (2) = 4.7; p = 0.09). After 4 weeks there was no statistically significant difference between the groups (H (2) = 4.8; p = 0.09). After 12 weeks CN increased NIBUT statistically significant from 9.9 ± 5.3 seconds at baseline to 15.5 ± 5.6 seconds (z = -2.4; p = 0.04). The effect size was r = 0.4. This represents a medium effect. F6H8 increased NIBUT from 12.4 ± 5.9 seconds at baseline to 16.9 ± 4.7 seconds (z = -2.6; p = 0.02) after 12 weeks ( | PMC9847907 |
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NIBUT at baseline and consecutive measurements. | perfluorohexyloctane | The NIBUT at 4 and 12 weeks were compared with the NIBUT of the baseline using the Wilcoxon test. All p-values were adjusted for 2 comparisons according to the Bonferroni method. An asterisk with the corresponding p-value indicates a significant change compared to the baseline. NIBUT = non-invasive tear break-up time; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.Both interventional groups had a comparably increased MGD score ( | PMC9847907 |
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Meibomian gland scores of the upper and lower eyelid. | MEIBOMIAN GLAND DYSFUNCTION | Grade 0: No loss of Meibomian glands; Grade 1: Loss of Meibomian glands less than one third of the total density on the eyelid; Grade 2: Loss between one and two thirds of the total density of the glands on the eyelid; Grade 3: Loss of glands is greater than two-thirds of the total density of glands on the eyelid; MGD = Meibomian gland dysfunction; CN = cationic nanoemulsion; F6H8 = perfluorohexyloctane.There were no harms observed in either group. | PMC9847907 |
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Discussion | hyperkeratinization, HOA, disorders of the tear film [, Obstruction of meibomian ducts | PATHOGENESIS, CORNEA | Previous studies have shown that HOA not only occur because of irregularities of the cornea, but also because of disorders of the tear film [Our study showed that LLT and HOA increase immediately after application of a cationic nanoemulsion of lipids (CN), although no correlation was found between the two parameters. Application of the lipophilic semifluorinated alkane (SFA), F6H8, did not increase the LLT. The increase of LLT shortly after application of CN is in accordance with literature [By contrast, F6H8 did not increase of HOA immediately after application. Agarwal et al. used a high-speed camera to visualize the impact of F6H8 on the tear film surface [Obstruction of meibomian ducts, hyperkeratinization and increased viscosity are major drivers in the pathogenesis of MGD [Considering the significant improvement of LLT, it is still surprising that we could not measure any change in aberrations. Montés-Micó et al. postulated that the lack of tears does not necessarily lead to higher aberrations in DED [F6H8 and CN increased the tear-break-up time (TBUT), which is in line with literature [There are limitations to our study. First, the integrity and stability of the tear film are dependent on many factors, including exogenous ones. The tear film is influenced by the sequence of examinations (which was standardized in our study), weather [Second, different devices for measuring HOA can only be compared to a limited extent. In a study that compared several aberrometers, the Visual Function Analyzer (Tracey Technologies, Houston Texas, USA) deviated significantly from other aberrometers in measuring the RMS values [Third, in cohort B the control group consisted of healthy individuals without DED, with a higher (i.e. normal) lipid layer thickness of > 75 ICU. While this limits comparison of the three groups at baseline, it also helped to demonstrate that F6H8 leads to normalization of the LLT.Fourth, the presented results are based on this specific population, and future studies (on other populations) are warranted to justify the hypothesis.In conclusion, the significant change in the lipid layer of the tear film caused by application of the lipid-based tear supplements studied, had no influence on higher-order aberrations in short- and long-term applications and thus should not have a negative impact on visual quality. | PMC9847907 |
References | PMC9847907 |
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Abstract | Members of the NINJA Collaborative are co-authors of this study and are listed under the heading Collaborators.Presented to the International Federation for Societies for Surgery of the Hand, London, UK, June 2022 | PMC7614411 |
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Background | injuries | Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. | PMC7614411 |
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Methods | surgical-site infection | A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. | PMC7614411 |
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Results | surgical-site infections | Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was €84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm ( | PMC7614411 |
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Conclusion | infection | INFECTION | After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving. Registration number: ISRCTN44551796 (Nail bed injuries in children are common. This study shows that, after performing a nail bed repair, it is more expensive to replace the nail plate and provides no benefit over discarding it. | PMC7614411 |
Introduction | synechiae, hand injury, pain, reduction of infection, injuries | SYNECHIAE | Nail bed injuries are the most common hand injury in childrenThe rationale for replacing the nail plate includes protection of the repair, reduction of infection, less pain at dressing changes, and splinting of the nail fold to prevent synechiae. The Cochrane reviewA pilot RCT informed the design and conduct of this definitive trial comparing replacing or discarding the fingernail after nail bed repair, and demonstrated that a large RCT was feasible | PMC7614411 |
Methods | The UK South Central Research Ethics Committee approved this study on 20 February 2018 (18/SC/0024). | PMC7614411 |
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Trial design and participants | infected injury, fracture | NAIL DISEASE | The NINJA (Nail bed INJury Analysis) trial was a multicentre, pragmatic two-arm parallel-group superiority RCT. The trial protocol and statistical and health economic analysis plans have been publishedParticipants were recruited from 20 UK National Health Service (NHS) hand surgery units. Inclusion criteria were: all children aged less than 16 years; a nail bed injury occurring within 48 h of presentation believed to require surgical repair; ability of patients, parents or guardians to give consent to inclusion and complete follow-up; and injury to a single finger. Patients were excluded if they had: an infected injury; underlying nail disease or deformity in the injured finger or contralateral finger before injury; a distal phalanx fracture requiring fixation; amputation; loss of part or all of the nail bed requiring reconstruction; and multiple nail bed injuries. Nail bed injuries extending to the nail fold were accepted. | PMC7614411 |
Interventions | PMC7614411 |
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Intervention 1: replace fingernail or substitute | Following debridement and suturing of the nail bed, the fingernail was replaced and secured with a figure-of-eight suture using Vicryl Rapide™ (Bridgewater, NJ) suture. A low-adherent dressing was applied. If the fingernail could not be replaced (for example owing to damage or loss), a substitute was chosen by the operating surgeon (such as foil). | PMC7614411 |
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Intervention 2: discard fingernail | Following debridement and suturing of the nail bed, the fingernail was discarded, and a low-adherent dressing applied. The dressing was not used to splint open the nail fold. | PMC7614411 |
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Outcomes | Baseline assessments were performed on the day of the operation before randomization, but after consent to participation had been provided. Follow-up assessments involved a clinical appointment between 7 and 10 days after operation, and a participant-reported questionnaire, sent via text, e-mail or post, at 7–10 days after operation, and at 4 months with a reporting window of up to 12 months. | PMC7614411 |
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Co-primary outcome measures | PMC7614411 |
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Surgical-site infection at 7–10 days | surgical-site infection, swelling, erythema, purulent, pain, SSI, tenderness | ERYTHEMA | The clinical research nurse or surgeon assessed the fingertip for evidence of surgical-site infection (SSI). Diagnosis of SSI was based on the presence of pain, swelling, tenderness, erythema, or purulent discharge. Definitive SSI had the addition of an organism isolated by culture or Gram stain | PMC7614411 |
Cosmetic appearance of the nail | The cosmetic appearance of the fingernail was assessed using the Oxford Fingernail Appearance Score (OFNAS) | PMC7614411 |
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Secondary outcome measures | SSI, pain | Secondary outcome measures collected were health-related quality of life using EuroQol Five Dimensions EQ-5D-Y™ (EuroQol Group, Rotterdam, the Netherlands), pain at first dressing change (measured using a 3-point Likert scale by children, participant or parent-assessed if the former was not able), SSI by 4 months, and participant (3-point Likert scale completed if able) and parent (0–100 scale) assessment of nail appearance at 4 months | PMC7614411 |
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Sample size | infection | INFECTION | The sample size for NINJA was based on observed infection rates in previous studies and on the cosmetic outcome in the NINJA-P study. The sample size of 416 was based on a clinically important difference of 7 per cent in the proportion of patients with an SSI between the two treatment groups, as well as a 15 per cent difference between treatment groups in the proportion of those achieving an optimal result in terms of the cosmetic appearance of the nail. These differences were chosen to provide 90 per cent power at a two-sided 5 per cent level of significance, with no adjustment made for multiple comparisons. | PMC7614411 |
Randomization and masking | RECRUITMENT | A computer-generated sequence was used to randomize participants using an allocation ratio of 1 : 1. Randomization was stratified according to recruitment site only, and treatment group numbers were balanced using sequences of random permuted blocks of sizes 2 and 4. Randomization was undertaken by a member of the research team once the participant had reached the operating theatre. Neither the surgeons nor participants could be masked. The cosmetic outcome assessment was performed by masked independent researchers. | PMC7614411 |
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Statistical analysis | infection, infections | REGRESSION, INFECTION, RECRUITMENT, INFECTIONS | Statistical analyses followed the statistical and health economic analysis planThe co-primary outcome SSI was analysed using logistic regression, adjusting for recruitment site as the only stratification factor using the cluster robust option in StataThe cost-effectiveness analysis took a time horizon of up to 12 months and estimated the cost per infection avoided, using the primary outcome measure from the trial (infections at 7 days). The cost of operating time was included. Further information about the cost-effectiveness analysis is provided in the statistical and health economic analysis plan, and detailed methods and results of the economic evaluation will be reported separately. Confidence intervals were estimated using bootstrapping and included multiple imputation of missing data. Cost is presented in Euros based on an exchange rate of 1 GBP = 1.126 EUR on 8th February 2023. | PMC7614411 |
Patient and public involvement | infection | INFECTION, SECONDARY | Patients and the public were involved from the start of the programme of research during the development of the initial pilot study and this definitive RCT. A parent/patient survey helped to set the primary and secondary outcomes, for example the decision to have co-primary outcomes of infection and cosmetic appearance. A patient representative was a trial co-investigator, a member of the trial management group, and involved at every stage of study design and delivery. They provided advice on the burden of participation, provision of patient information, and subsequent dissemination. | PMC7614411 |
Results | surgical-site infection, ’ fingernails, vomiting, pain, infection | ADVERSE EVENTS, INFECTION, SECONDARY, ADVERSE EVENT, PARONYCHIA | Some 451 patients were recruited between July 2018 and December 2019; 224 patients were allocated to the nail-discarded arm and 227 to the nail-replaced arm (Baseline characteristics of participants according to intervention groupValues are Compliance with treatment allocated at randomizationValues are The type of anaesthetic used was similar in each group, as were perioperative antibiotics (Two serious adverse events were recorded. The first patient developed paronychia (infection around the nail plate) approximately 4 months after surgery, requiring readmission to hospital and removal of a nail spicule. This was an expected adverse event and determined to be related to the surgical intervention. The second patient suffered a reaction to general anaesthetic causing vomiting and intolerance to anything orally, leading to a 1-week stay in hospital for hydration. This was an unexpected adverse event and was deemed unlikely to be related to the surgical intervention.For the co-primary outcome SSI, 440 patients had data available for the primary analysis (97.6 per cent of those randomized; 218 in discarded arm, 222 in replaced arm) (Analysis of surgical-site infection at around 7 daysValues are Assessors and parents scored patients’ fingernails using the OFNAS for the cosmetic co-primary outcome (Main, secondary, and subgroup analyses of Oxford Finger Nail Appearance Score cosmetic outcome*Values in parentheses are 95% confidence intervals; effect sizes are shown as ORs, except †probability that Oxford Finger Nail Appearance Score There was no significant difference in cosmetic appearance between groups in the co-primary outcome of cosmetic appearance, as measured by the OFNAS (The adjusted secondary analysis did not identify any statistically significant difference in OFNAS values between the two treatment groups (OR 0.70, 95 per cent c.i. 0.43 to 1.12; The assessor scores did not indicate a difference between the nail-replaced and nail- discarded groups. However, the scores given by the parents suggested that there was a statistically significant difference in favour of the nail-discarded group. The treatment by subgroup interaction term was statistically significant (OR 0.24, 95 per cent c.i.: 0.06, 0.96. Preoperative antibiotic use did not affect the difference in cosmetic appearance between the two treatment groups as measured by the OFNAS (There were no statistical differences between groups for the secondary outcomes, including pain at dressing change, late incidence of SSI (up to 12 months), parent/child satisfaction with nail appearance, and EQ-5D-Y™ index scores ( | PMC7614411 |
Economic evaluation | infections | INFECTIONS | The base-case economic evaluation showed that the mean NHS cost in the first 4–12 months after nail bed repair surgery was £75.07 (95 per cent c.i. 30.05 to 124.11) higher in the replace group than the discard group (After multiple imputation of missing data, the mean incidence of infections by 7–10 days was 0.0137 (95 per cent c.i. −0.0091 to 0.0352) per patient higher in the replace group than in the discard group ( | PMC7614411 |
Discussion | injury severities, infections, fingertip injury, pain, infection, trauma | INFECTION, INFECTIONS | The NINJA trial showed no statistically significant difference in early (day 7) infections or final cosmetic outcome between patients who had the fingernail replaced and those who had the fingernail discarded after nail bed repair. The early infection rate (day 7) was 2.2 per cent in the nail-replaced group There was no difference between groups in cosmetic outcome or satisfaction with appearance, suggesting that replacing the nail, or not, does not influence the appearance of the new nail that grows out.There was no evidence that replacing the nail after surgery can offer reduced pain at dressing change. A slightly larger number of children experienced pain in the nail-discarded group (47.8 per cent) compared with the nail-replaced group (40.5 per cent) but this did not reach statistical significance.The health economic analysis showed that replacing the nail was associated with significantly longer operating time and cost. This resulted in a statistically significant cost saving of £75 per patient if the nail was discarded. Nail bed repair is the commonest paediatric hand trauma operation performed globally; this represents a significant cost saving to healthcare systems. As 96 per cent of nail bed repair procedures currently involve replacement of the nailThe NINJA trial is the first large RCT investigating outcomes after paediatric fingertip injury, and provides strong evidence to direct practice. Development of the OFNAS has provided a more evidence-based tool for assessing nail cosmesis for future studies. The infection rate was lower than anticipated in both groups, and will have contributed to the lower level of statistical precision. The very low rate of missing data at 7–10 days for the infection rate is a great strength, but the later missing data at the final cosmesis time point is a limitation. However, the sensitivity analysis which looked at the potential impact of missing data (using the RCTmiss command) suggested the finding was robust. A further limitation was the necessary changeover of cosmetic assessment method to include parents reporting a large proportion of the final assessment.Compared with the published literature, this study provides more robust data on the potential harms and likely outcome of patients undergoing nail bed repair. This will support the counselling of parents and older children. Previous non-randomized studies reported higher rates of infection perhaps owing to the limitations of non-randomized retrospective studiesWhether to replace or discard the nail plate has been a longstanding source of contention among surgeons. This study has addressed this issue and laid the foundation for asking a further question: Should the nail bed be repaired or not? Nail bed injuries encompass a wide spectrum of injury severities. For instance, a sizeable proportion might be amenable to being cleaned in the emergency department and dressed with adhesive strips. | PMC7614411 |
Collaborators | A. Arnaout, K. Walsh, P. | SUTTON, FOX, LARSEN, SLOUGH | NINJA Collaborative: A. Mertic, H. Gerrish, K. Cranmer, N. Fox, P. Dutta (Broomfield Hospital, Chelmsford, UK); G. Vissers, P. Costa, R. Irri, G. McArthur, M. Horwitz (Chelsea and Westminster Hospital, London, UK); A. Sleiwah, H. Jephson, M. Deeley, R. Nicholas, Z. Vinnicombe, A. Nicola (Guys and St Thomas' Hospitals, London, UK); C. Bing Chuo, C. Milner, J. Heaney, J. Totty, M. Fleet, M. Faheem Khadim, P. Williams, S. Bibawy, A. Round, R. Pinder (Hull Royal Infirmary, Hull, UK); A. Plonczak, G. Lawton, D. Kennedy (St Mary's Hospital, London, UK); A. Bennett, A. Fadulelmola, J. James, E. Reay (James Cook Hospital, Middleborough, UK); K. Beadon, T. Cameron, Z. Oliver, K. Wensley, S. Dupré, J. Rodriguez, D. Furniss (John Racliffe Hospital, Oxford, UK); M. Gale (Kings Mill Hospital, Sutton in Ashfield, UK); A. Knight, J. Tulip, L. Turner, L. Wellings, M. Allen, R. Wade, V. Itte, G. Bourke (Leeds General Infirmary, Leeds, UK); N. Kumar, S. O'Sullivan, J. WM Jones (Peterborough City Hospital, Peterborough, UK); K. Young, K. Taylor, O. Dawood, S. Booth, L. Giwa, R. Pearl (Queen Victoria Hospital, East Grinstead, UK); A. Coutts, R. Hawkins, A. Mostafa, T. Nisbett, P. Riddlestone (Royal Cornwall Hospital, Truro, UK); A. Selby, C. Uzoho, D. Chasiouras, LC. Bainbridge (Royal Derby Hospital, Derby, UK); T. Buick, W. Lam (Royal Hopsital for Sick Children, Edinburgh, UK); B. Baker, K. Walsh, K. Keating, R. Dalan, M. Shah (Royal Manchester Children's Hospital, Manchester, UK); D. Mead, S. Diment, M. Nicolau (Salisbury District Hospital, Salisbury, UK); B. Smeeton, D. Thomson, N. Senior, J. Moledina, J. Colville (St George's Hospital, London, UK); K. Manso, M. Song, O. Manley, P. Drury, R. Kerstein, W. Cobb, J. Wormald, R. Shirley (Stoke Mandeville Hospital, Aylesbury, UK); A. Tan, A. Arnaout, C. Cruz, N. Brice, N. Segaren, N. Joji, R. Chawla, S. Hassanin, R. Adami, H. Ridha (The Lister Hospital, Stevenage, UK); A. Cook, L. Symington, R. Long, S. Dustagheer (The Ulster Hospital, Belfast, UK); H. Jarvis, M. Larsen, M. Williams, R. Trickett (University Hospital of Wales, Cardiff, UK); D. Miles (University of Essex, Colchester, UK); A. Pai, C. Honeywell, C. Brady, S. Madhavan, V. Manou, G. Phillips, R. Baker (Wexham Park Hospital, Slough, UK).CONSORT diagram for the NINJA trial OFNAS,#Oxford Finger Nail Appearance Score | PMC7614411 |
Supplementary Material | Click here for additional data file. | PMC7614411 |
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Acknowledgements | P. | A.J. and A.V.H.G. are joint first authors of this article. This study was managed by the Royal College of Surgeons Oxford Surgical Intervention Trials Unit (SITU; supported by Oxford NIHR Biomedical Research Centre) and conducted as part of the portfolio of trials in the registered UK Clinical Research Collaboration (UKCRC) Oxford Clinical Trials Research Unit (OCTRU) at the University of Oxford. It followed their Standard Operating Procedures, ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki, and any applicable regulatory requirements. The authors thank the trial sponsors, University of Oxford, staff at the SITU and OCTRU trial units, and the Reconstructive Surgery Trials Network who supported this trial; participants and their families, principal investigators and their teams at each of the NINJA sites; the independent trial steering committee—A. Karantana (Chair), C. Hewitt, G. Smith, S. Petrou, H. Connolly, R. Harman, R. Nandi; the Data Monitoring Committee—G. Lawton (Chair), A. Elders, D. Kennedy; and the patient co-applicants—D. Blanche and S. Snelling for their time and support throughout the trial. The following contributed to aspects of the study conduct: A. Riddell, A. Bonges, A. Diver, B. Tallon, C. Coapes, C. Harrison, D. Berwick, D. Miller, E. Pardoe, E. Glass, I. King, I. Yonjan Lama, I. Teo, J. Ting, J. Summers, J. Jeevaratnam, J. Luck, J. Ruston, K. Finlay, K. Nundlall, L. Kottam, M. Mikhail, M.-C. Miller, M. Singh, M. Kharashgah, M. Shahid Ikram, N. Silberras, N. Johnson, N. Modi, N. Mackie, P. Kumar Patel, R. Mistry, and R. Burton.An executive summary of the findings was sent to all trial participants. Once the findings have been published, the details will be provided to patient/public groups and professional organizations with a request to disseminate to their membership. | PMC7614411 |
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Funding | The trial was funded by the National Institute for Health and Care Research (NIHR), Research for Patient Benefit programme (PB-PG-1215-20041), and supported by the NIHR Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The study funders had no role in the study design, data collection, data analysis, interpretation, writing of the manuscript, or decision to submit for publication. All authors had access to all study data and take responsibility for its integrity and the accuracy of the data analysis. H.D. is partly funded by an NIHR Senior Research Fellowship through the Oxford BRC. D.J.B. is partly funded by the Royal College of Surgeons of England and the Rosetrees Trust. The trial sponsor was the University of Oxford. | PMC7614411 |
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Author contributions | Ee, Heidi Fletcher | MAY | Abilash Jain (Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Visualization, Writing—original draft, Writing—review & editing), Aina Grieg (Conceptualization, Funding acquisition, Investigation, Methodology, Writing—review & editing), Amy Taylor (Investigation, Methodology, Project administration, Resources, Writing—review & editing), Cushla Cooper (Data curation, Funding acquisition, Investigation, Methodology, Project administration, Validation, Writing—review & editing), Loretta Davies (Investigation, Methodology, Project administration, Validation, Writing—review & editing), Akiko Greshon (Data curation, Formal analysis, Methodology, Validation, Writing—review & editing), Heidi Fletcher (Formal analysis, Investigation, Methodology, Project administration, Writing—review & editing), Adam Sierakowski (Conceptualization, Funding acquisition, Investigation, Methodology, Writing—review & editing), Melina Dritsaki (Data curation, Formal analysis, Methodology, Writing—review & editing), An Nguyen (Formal analysis, Investigation, Methodology, Writing—review & editing), May Ee Png (Formal analysis, Investigation, Validation, Writing—review & editing), Jamie Stokes (Formal analysis, Investigation, Methodology, Project administration, Validation, Writing—review & editing), Helen Dakin (Formal analysis, Investigation, Methodology, Supervision, Validation, Writing—review & editing), Jonathan Cook (Data curation, Formal analysis, Funding acquisition, Investigation, Validation, Writing—review & editing), David Beard (Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Writing—review & editing), and Matthew Gardiner (Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing—original draft). | PMC7614411 |
Disclosure | The authors declare no conflict of interest. | PMC7614411 |
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Supplementary material | PMC7614411 |
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Data availability | Requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to SITU at | PMC7614411 |
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References | PMC7614411 |
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Objectives | There is no practical approach for accurately predicting the efficacy of non-vascularized bone grafting (NVBG) and guiding its optimal procedure. | PMC10712171 |
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Materials and methods | This study enrolled 153 patients with 182 hips that underwent NVBG procedures. The patients were randomly divided into a training cohort (n = 130) and a validation cohort (n = 52). In the training cohort, radiomics model, clinical model, and combined radiomics-clinical (C-R) model were constructed using Rad-scores and clinical predictors to predict the efficacy of NVBG. The optimal model was visualized by a nomogram and assessed by decision curve analysis (DCA). 128 hips that underwent successful NVBG were then randomized into a new training cohort (n = 92) and a new validation cohort (n = 36), and three models were constructed and validated to predict the choice of NVBG procedure. | PMC10712171 |
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Results | Japanese Investigation Committee (JIC) classification, exposure to risk factors postoperative, and Rad-scores consisting of four radiomics features were independent predictors for the efficacy of NVBG ( | PMC10712171 |
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Conclusion | The approach integrated by CT radiomics and clinical predictors can be visually and quantitatively applied to predict the efficacy and guide the choice of NVBG procedure with great predictive accuracy. | PMC10712171 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12891-023-07095-1. | PMC10712171 |
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Keywords | PMC10712171 |
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Introduction | ONFH, debilitating disease | OSTEONECROSIS OF THE FEMORAL HEAD | Osteonecrosis of the femoral head (ONFH) is a rapidly progressive and debilitating disease [Non-vascularized bone grafting (NVBG) is a viable treatment for pre- and early post-collapse ONFH [The concept of radiomics has emerged as a promising approach to medical imaging with the rapid development of medical artificial intelligence technology [Our institution has been performing NVBG using the Phemister procedure and lightbulb procedure, with a large number of cases, detailed clinical and radiographic data, and medium to long-term follow-up. Therefore, we developed a visual and quantitative assessment approach using data from patients and evaluated its performance internally. Our study aims to provide valuable insights into the optimal selection and efficacy of NVBG procedures for hip preservation using CT radiomics and clinical predictors. We seek to determine suitable patients for hip preservation with NVBG, to identify the most appropriate procedure, and to explore strategies to improve the success rate of hip preservation. | PMC10712171 |
Materials and methods | PMC10712171 |
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Clinical data | Clinical data associated with the efficacy of hip preservation, as reported in the literature [ | PMC10712171 |
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CT image acquisition | All patients underwent preoperative CT scans of bilateral hips, with images acquired from the PACS system in DICOM format. CT scans were performed using a Brilliance CT scanner (128-row, Philips Healthcare, Netherlands) or a LightSpeed VCT scanner (64-row, GE Healthcare, USA), with scan parameters including tube voltage of 120-140 kV, tube current of 220-680 mA, exposure time of 250–800 mS, layer thickness of 1.0–3.0 mm, layer spacing of 1.0–3.0 mm, and matrix sizes of 512 × 512.The resampling process was carried out using the bilinear interpolation method, with the resampling layer thickness and layer spacing set at 1 mm. Images were then imported into 3D Slicer ( | PMC10712171 |
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ROI segmentation and feature extraction | fracture | OSTEOSCLEROSIS | The zone with abnormal density, such as osteosclerosis, cystic change, and subchondral bone fracture, is defined as the region of interest (ROI). These ROIs were manually segmented and outlined in coronal, sagittal, and axial positions in the bone window (window width 1500HU, window level 400U) by a senior radiologist (**) and a senior orthopedic surgeon (**) to produce 3D ROIs (Fig. | PMC10712171 |
Construction and application of models for the efficacy of NVBG | To determine who is suitable for hip preservation with NVBG, we constructed predictive models for the efficacy of NVBG. The hips were randomly divided into a training cohort (n = 130) and a validation cohort (n = 52) at a ratio of 7:3 using computer-generated random numbers to ensure that there was no overlap of hips in the two datasets. In the training cohort, clinical data were analyzed by univariate and multivariate analyses to screen for clinical predictors. The least absolute shrinkage and selection operator (LASSO) method was used to select the most useful radiomics features for prediction, and the radiomics score (Rad-scores) was calculated for each patient through a linear combination of selected features weighted according to their respective coefficients.Three models were constructed in the training cohort based on the extracted features: the Clinical model, Radiomics model, and C-R model based on the combination of clinical predictors and Rad-scores. The predictive performance of the three models was evaluated and validated in both cohorts through the receiver operating characteristic curve (ROC), area under curve (AUC), and DeLong test to compare the AUCs. The predictive performance of each model was assessed based on AUC, sensitivity, and specificity, while the goodness of fit of each model was evaluated using a calibration curve with Hosmer-Lemeshow test. To provide clinicians with a quantitative approach for assessing the efficacy of NVBG, we visualized the optimal model by constructing a nomogram and estimated the clinical utility using Decision Curve Analysis (DCA). DCA was performed by calculating the net benefits for a range of threshold probabilities in both the training and validation cohorts. | PMC10712171 |
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Construction and application of model for the choice of NVBG procedures | To determine which NVBG procedure should be chosen, we constructed predictive models for the choice of NVBG procedures. Of the 128 hips that underwent successful NVBG, they were divided into a new training cohort (n = 92) and a validation cohort (n = 36) at a ratio of 7:3 to ensure that there was no overlap of hips in the two datasets. Radiomics features and clinical predictors were extracted from patients, with the choice of NVBG procedures used as the dependent variable. The predictive models were then constructed and validated, with the optimal model visually quantified to assist in clinical procedure selection. | PMC10712171 |
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Statistical analysis | REGRESSION | All statistical tests were performed using SPSS 26.0 and R statistical software (version 1.2.5042, In R statistical software, we used the “glmnet” package to peform the LASSO regression analysis, while the survival curves were obtained using the “survminer” package. ROC curves were plotted using the “pROC” package, and calibration plots were constructed using the “resourceSelection” package. The nomogram was constructed with the use of the “rmda” package, while DCA was performed using both the “rmda” and “ggDCA” packages. | PMC10712171 |
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Results | PMC10712171 |
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Feature importance & performance of models for the efficacy of NVBG | There were statistically significant differences in JIC and exposure to risk factors postoperatively (Table
Univariate and multivariate analysis for efficacy of NVBG in the training cohort
Radiomics features selected by LASSO to determine the efficacy of NVBG (In the training cohort, the C-R model had an AUC of 0.818 (95% CI: 0.743–0.893), predicting sensitivity of 0.778 and specificity of 0.729 at the optimum cut-off of 0.308. In the validation cohort, the AUC of C-R model was 0.747 (95% CI: 0.564–0.930), with a predicting sensitivity of 0.556 and specificity of 0.860 at the optimum cut-off of 0.480 (Fig.
Performance of three models for predicting efficacy of NVBG
ROC curves (A nomogram was developed to visualize the C-R model (Fig.
Nomograms of the C-R model for predicting the efficacy of NVBG ( | PMC10712171 |
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Feature importance & performance of models for the choice of NVBG procedures | JIC classification was found to be an independent clinical predictor associated with the choice of procedures (Table
Univariate and multivariate analysis for the choice of NVBG procedures in the training cohortCompared to the other two models, the C-R model had superior prediction performance, with an AUC of 0.860 (95%CI, 0.781–0.939) in the training cohort and 0.800 (95% CI, 0.620 to 0.980) in the validation cohort (
Performance of three models for predicting the choice of NVBG procedures
ROC curves (The nomogram of the C-R model showed that patients with higher Rad-scores and types C1 and C2 of JIC classification should choose the lightbulb procedure, whereas patients with lower Rad-scores should choose hip preservation with the Phemister procedure (Fig. | PMC10712171 |
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Discussion | necrotic, necrosis | MCC, NECROTIC, NECROSIS | Currently, there is a general consensus in the academic community on the criteria for assessing the efficacy of hip preservation [Both procedures integrated in this study were NVBG, but they had some differences. The lightbulb procedure can expose most of the femoral head, allowing the operator to remove necrotic bone thoroughly and fill it with autologous or allogeneic bone under direct vision [In this study, we applied radiomics to hip preservation. We screened a total of four radiomics features related to efficacy and five related to NVBG procedures, which we divided into the following two categories: (1) Shape feature describing the 3D size and shape of the ROI-Elongation, it shows the relationship between the two largest principal components in the ROI shape, and (2) Texture features-GLCM and GLDM, including MCC for complexity of the texture, Dependence Non-Uniformity Normalized for the similarity of dependence throughout the image, Mean, Joint Average, and Median for gray level intensity within the ROI. These radiomics features reflect the correlation between the extent, size, and local signal intensity of the necrotic area and efficacy of NVBG & NVBG procedures at the microscopic level.Roger [JIC is an independent clinical predictive variable associated with the efficacy and choice of NVBG procedures, reflecting the extent of necrosis and the degree of involvement of the lateral column. The extent and location of necrosis of the femoral head are recognized factors in the prognosis of the femoral head, and the integrity of the anterolateral column plays a vital role in maintaining the function of the femoral head [Of the three models constructed based on the above predictive variables, the C-R model outperformed the clinical model and the Radiomics model, with higher specificity and sensitivity both in the training cohort and validation cohort. Radiomics refers to the comprehensive quantification of the necrotic area by applying massive quantitative imaging features at the microscopic level, which may reflect changes in the femoral head at the cellular and genetic levels, and provides more detailed information on the necrotic area and microenvironment that are complementary to visual features [However, our study has several limitations: (1) This study was a retrospective single-center design, resulting in a small sample size and limited variety of surgical procedures, so multi-center, prospective, and large sample validation should be considered in future studies; (2) Our nomograms weren’t validated on an independent, external validation cohort, which would influence the predictive performance of the models. Furthermore, nomograms represent static models or algorithms and cannot easily be updated, a single and static graph is difficult to summarize the modern predictive modeling techniques and algorithm developments [ | PMC10712171 |
Conclusion | In this study, we developed models using CT radiomics and clinical predictors to predict the efficacy and guide the choice of procedures in NVBG, which were visually and quantified by nomograms. Our proposed approach can be easily integrated into the clinical setting and widely used as a practical tool to predict the efficacy of NVBG preoperatively for suitable patient selection. This approach allows for the development of individualized and differentiated treatment plans without additional healthcare expenses. | PMC10712171 |
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Author contributions | Conceptualization, methodology and project administration were performed by Bin Du and Xin Liu. They contributed equally to this work and should be considered co-corresponding authors. Material preparation, data collection and analysis were performed by Hao Chen and Peng Xue. They contributed equally to this work and should be considered co-first authors. Software and validation were performed by Hongzhong Xi. Visualization and investigation were performed by Shuai He. Supervision was performed by Guangquan Sun. | PMC10712171 |
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Funding | This work was supported by the National Natural Science Foundation of China (82074471), Jiangsu Graduate Practice and Innovation Plan (No. SJCX22_0769) and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No.035062005001). | PMC10712171 |
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Data Availability | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10712171 |
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Declarations | PMC10712171 |
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Ethics approval and consent to participate | This study was approved by the ethics committee of the Affiliated Hospital of Nanjing University of Chinese Medicine approved this study (Ethical approval ID: 2023NL-001-01), which waived the requirement for individual consent due to the use of retrospective data. | PMC10712171 |
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Consent for publication | Not applicable. | PMC10712171 |
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Competing interests | The authors declare no competing interests. | PMC10712171 |
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References | PMC10712171 |
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Subject terms | hypotension | EVENTS, HYPOTENSIVE EPISODE, SIDE EFFECT, POSTOPERATIVE COMPLICATIONS | Reducing hypotension is crucial as hypotension is the most common side effect of spinal anesthesia, and in older patients with various comorbidities, it can lead to fatality. We hypothesized that continuous infusion of norepinephrine could effectively prevent hypotension in older patients undergoing hip surgery under spinal anesthesia with propofol sedation. The study randomly assigned patients aged ≥ 70 years to either a control (Group C, n = 35) or a norepinephrine group (Group N, n = 35). After spinal anesthesia, continuous infusion of propofol and normal saline or norepinephrine was initiated. The number of hypotensive episodes, the primary outcome, as well as other intraoperative hemodynamic events and postoperative complications were compared. In total, 67 patients were included in the final analysis. The number of hypotensive episodes was significantly higher in Group C than in Group N (Clinical trial registration number: KCT0005046 ( | PMC10686984 |
Introduction | Hypotension, hypotension | SIDE EFFECT | Hypotension is the most common side effect of spinal anesthesia (SA), especially in older individuals. High-segment sensory nerve block and advanced age are major risk factors for hypotension after SA | PMC10686984 |
Discussion | hypotension | HYPOTENSIVE EPISODE | We found that infusing norepinephrine under SA with propofol sedation during hip surgery in patients aged ≥ 70 years was effective in decreasing the number of hypotensive episodes per patient and the incidence of hypotension during SA with intravenous propofol infusion.Lower extremity surgery represents 24% of all interventions among patients aged ≥ 75 yearsAs the degree of hypotension is proportional to the height of the sympathetic nerve blockSeveral strategies, including intravenous fluid administration and vasopressors, have been considered to prevent the occurrence of hypotension after SA induction. Prophylactic administration of crystalloid before SA is effective at preventing hypotension, at least in some patientsThe use of alpha-agonists to treat hypotension associated with SA has been extensively studied in the field of obstetrics. Phenylephrine, a pure alpha1-adrenergic receptor agonist that has no direct effect on HR, showed a beneficial effect during SA for cesarean deliveryAlthough more than 100 definitions of hypotension are mentioned in the literature, Salmasi et al. found that there was no advantage to using relative over absolute thresholdsThis study had several limitations. First, PVi values were measured during spontaneous breathing. PVi is a measure of the variations in the pulse oximeter waveform over respiratory cycles in non-invasive and continuous manner. When mechanical ventilation is employed, PVi can be considered reliableIn conclusion, the present study showed that prophylactic norepinephrine continuous intravenous infusion prevented hypotensive episodes, reduced the occurrence of hypotension and the requirement of fluid, and increased the urine output in older patients undergoing unilateral hip surgery under SA with propofol sedation. | PMC10686984 |
Methods | This single-center, prospective, randomized controlled trial study was performed in a tertiary center in Seoul, Republic of Korea. After receiving approval from the Institutional Review Board of Asan Medical Center (approval date: April 13, 2020), this trial was registered on the Clinical Research Information Service ( | PMC10686984 |
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Study population and preparation | infection, allergy, dementia | UNCONTROLLED HYPERTENSION, CORONARY DISEASE, MITRAL STENOSIS, ALLERGY, HYPERTHYROIDISM, INFECTION, AORTIC STENOSIS, SEVERE, COAGULOPATHY | All older patients scheduled for unilateral primary hip surgery in the lateral position between 2020 August and 2021 June in the host institution were considered eligible for the study. Among them, we included patients who met the following criteria: (1) American Society of Anesthesiologists physical status class 1–3, and (2) age ≥ 70 years. We excluded patients with uncontrolled hypertension, hyperthyroidism, dementia, or symptomatic coronary disease; hemoglobin levels < 10 g/dL; a previous history of allergy to propofol, fentanyl, or bupivacaine; and those who were contraindicated for SA, including coagulopathy, severe aortic stenosis, severe mitral stenosis, and active infection on the lumbar region. Patients who refused to participate in this study or for whom norepinephrine was contraindicated were also excluded.All included patients were randomly allocated into Group C (n = 35) and Group N (n = 35). Randomization was conducted using a computer-generated randomization program ( | PMC10686984 |
Preoperative management | hip fracture, pain | SECONDARY | The preoperative management was not strictly controlled in this study. However, according to our center's preoperative management protocol for surgical patients, all patients fasted from midnight on the day of surgery. Meanwhile, a maintenance volume of fluid was administered. In patients with hip fracture, pain management was provided during the preoperative period. The patients were instructed to remain at bed rest for stabilization, and if their pain score using numerical rating scale was > 4 points, tramadol hydrochloride 50 mg was administered as a first-line treatment, followed by hydromorphone hydrochloride 1 mg as a secondary treatment. Premedication was not administered to any of the patients preoperatively. | PMC10686984 |
Anesthesia and surgery | normovolemia | DECUBITUS | After patients arrived in the operating room, standard monitoring, including non-invasive blood pressure, electrocardiography, and pulse oximetry was initiated. Non-invasive blood pressure (NIBP) was measured in the contralateral arm to the surgical site with 2.5-min intervals throughout the surgery, while electrocardiography, and pulse oximetry were monitored continuously. To maintain normovolemia, PVi (Radical-7®, Masimo Corp., Irvine, CA, USA), a dynamic index of fluid responsiveness, was also continuously monitored on ipsilateral arm to the surgical site. Oxygen was supplied at 5–6 L/min via a simple facemask.An intravenous peripheral line was accessed at the ipsilateral hand or forearm, and the patients were positioned into their lateral decubitus position. The standard practice was to position patients in a lateral decubitus position with the surgical site downward. However, if the patients expressed discomfort regarding the position, they were placed in a lateral decubitus position with the surgical site upward. SA was performed with hyperbaric bupivacaine 10 mg and fentanyl 15 µg, using 25-gauge needle after skin disinfection. Then, the patients were returned to the supine position, and the insertion of the foley catheter was performed. Intravenous co-hydration with 300 mL of crystalloid was initiated immediately after completion of the intrathecal injection. The success and level of SA was examined on both the left and right sides at 5 min after the intrathecal injection. As all surgeries were conducted in the lateral decubitus position, patients were positioned laterally with the surgical site facing upward. Norepinephrine or normal saline and propofol were connected, and the continuous infusion of norepinephrine or normal saline was initiated through the inserted peripheral line. Propofol was also infused using a target-controlled infusion system (effect-site concentration 1.0–1.5 µg/mL), and was adjusted to maintain a BIS between 60 and 80 and modified observer’s alertness/sedation scale of 3 (responds only after name is called loudly and/or repeatedly). The intraoperative volume status was monitored using PVi values. Considering that the patients were spontaneously breathing and referencing the results of a previous study, fluid was administered to maintain PVi < 19% | PMC10686984 |
Definition of hemodynamic events and management | hypotensive, Hypotension, hypotension, Hypertension | EVENT, HYPOTENSIVE, HYPERTENSION | Hypotension was defined as MBP < 65 mmHg. When a hypotensive event occurred, phenylephrine 100 µg was injected intravenously as a rescue drug, regardless of the group. Measurements of NIBP were performed until 1 h postoperatively, during which time phenylephrine 100 µg was also administered in case of hypotension. Hypertension was defined as systolic blood pressure (SBP) > 160 mmHg, or an increase in MBP > 20% from the baseline value. Baseline MBP (MBP | PMC10686984 |
Outcome measures and data collections | delirium, neurologic complications, pneumonia, arrhythmia, desaturation, ischemic accident, hypotension, renal dysfunction, acute kidney injury | PLEURAL EFFUSION, PNEUMONIA, ARRHYTHMIA, POSTOPERATIVE COMPLICATIONS, POSTOPERATIVE COMPLICATION, PULMONARY EDEMA, CEREBROVASCULAR ACCIDENT, HYPOTENSIVE EPISODE, SECONDARY, CONGESTIVE HEART FAILURE, ACUTE CORONARY SYNDROME, RESPIRATORY COMPLICATIONS, EVENTS, KIDNEY DISEASE, NEUROLOGIC COMPLICATION, CARDIOVASCULAR COMPLICATIONS, COMPLICATIONS | The primary outcome of this study was the number of hypotensive episodes that occurred during surgery. The secondary outcomes were other hemodynamic events during surgery and postoperative complications during the hospitalization. Postoperative complications included cardiovascular complications (i.e., acute coronary syndrome, congestive heart failure, hypotension, and arrhythmia), neurologic complications (i.e., transient ischemic accident and cerebrovascular accident), respiratory complications (i.e., pneumonia, pulmonary edema, pleural effusion, and desaturation), delirium, renal dysfunction (i.e., acute kidney injury based on Kidney Disease: Improving Global Outcomes criteria), and other complications. | PMC10686984 |
Statistical analysis | HYPOTENSIVE EPISODE | No prior study has clearly identified hypotensive episodes in older patients undergoing SAwith propofol sedation. Therefore, we determined the sample size using Poisson means. The Poisson means were derived from the retrospective review of our clinical experiences. There were 4.75 hypotensive episodes during a single surgery in older patients who underwent hip surgery under SA with propofol sedation without any continuous infusion of vasopressor, whereas there were 1.67 hypotensive episodes with the continuous infusion of norepinephrine. However, as we had only limited experience on the preventive use of norepinephrine, to ensure a sufficient number of patients, we assumed a Poisson mean of double that of 1.67, which is 3.34, for the treatment group. The calculated sample size, with α = 0.05 and power = 80% using a two-sample and two-sided equality test, was 32 patients in each group. Therefore, after considering possible dropouts, we decided to assign 35 patients into each group.The Poisson test was used to analyze the number of hypotensive episodes. Other continuous variables were analyzed using Student’s | PMC10686984 |
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Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-48178-2. | PMC10686984 |
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Acknowledgements | None. | PMC10686984 |
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Author contributions | H.K. and H.J.K. conceived and designed the study. S.L. collected clinical samples and data. H.K., W.U.K., J.C., S.W.P., K.S.K., and H.J.K. analyzed the data and contributed to data interpretation. H.K. and H.J.K. wrote the first draft of the manuscript. H.K., W.U.K., Y.J.R., and H.J.K. reviewed the manuscript. All authors approved the final manuscript for submission. | PMC10686984 |
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Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10686984 |
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Data availability | The datasets used and analyzed in the current study are available from the corresponding author on reasonable request. | PMC10686984 |
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Competing interests | The authors declare no competing interests. | PMC10686984 |
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References | PMC10686984 |
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Background | Metabolic derangements, inflammation, colorectal cancer, CRC | METABOLIC DERANGEMENT, COLORECTAL CANCER, INFLAMMATION | Metabolic derangements and systemic inflammation are related to the progression of colorectal cancer (CRC) and the prognoses of these patients. The survival of stage II and III CRC patients existed considerable heterogeneity highlighting the urgent need for new prediction models. This study aimed to develop and validate prognostic nomograms based on preoperative serum liver enzyme as well as evaluate the clinical utility. | PMC10318767 |
Methods | A total of 4014 stage II/III primary CRC patients pathologically diagnosed from January 2007 to December 2013 were included in this study. These patients were randomly divided into a training set ( | PMC10318767 |
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Results | DFS of stage II/III, CRC | Among seven preoperative serum liver enzyme markers, aspartate aminotransferase-to-alanine aminotransferase ratio (De Ritis ratio) was identified as an independent factor for predicting both OS and DFS of stage II/III CRC patients. The nomograms incorporated De Ritis ratio and significant clinicopathological features achieved good accuracy in terms of OS and DFS prediction, with C-index of 0.715 and 0.692, respectively. The calibration curve showed good agreement between prediction by nomogram and actual observation. The results of time-dependent ROC and decision curve analyses suggested that the nomograms had improved discrimination and greater clinical benefits compared with TNM and AJCC staging. | PMC10318767 |
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Conclusions | CRC | De Ritis ratio was an independent predictor in predicting both the OS and DFS of patients with stage II/III CRC. Nomograms based on De Ritis ratio and clinicopathological features showed better clinical utility, which is expected to help clinicians develop appropriate individual treatment strategies for patients with stage II /III CRC. | PMC10318767 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12885-023-11125-5. | PMC10318767 |
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Keywords | PMC10318767 |
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Background | colorectal cancer, tumor, metabolic derangements, CRC, cancer death, cancer, deaths | CANCER, COLORECTAL CANCER, TUMOR | Globally, colorectal cancer (CRC) is the second leading cause of cancer death, accounting for an estimated 915,880 deaths in 2020 [Metabolic reprogramming is a hallmark of cancer. Accumulating evidence suggests that metabolic derangements provide abundant energy, nutrients, and redox requirements for tumor cells, which contributes to the occurrence and progression of tumor [Therefore, our study evaluated the prognostic values of seven preoperative serum liver enzyme markers. Considering the ability of a single serum biomarker may be insufficient, we incorporated significant serum liver enzyme markers and clinicopathological features to develop prognostic nomograms for a better individual CRC patient’s survival prediction. | PMC10318767 |
Methods | PMC10318767 |
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Study population | CRC | A total of 4392 primary stage II/III CRC patients confirmed by pathological diagnosis were enrolled in this retrospective cohort. These patients underwent radical resection surgery in the Third Affiliated Hospital of Harbin Medical University from January 2007 to December 2013. Patients who met one or more of the following exclusion criteria were excluded (Fig. Detailed flow chart of patient selection in this studyAt last, 4014 stage II/III CRC patients were included in this study and these patients were randomly divided into a training set (60%) and a testing set (40%). Throughout this article, the term ‘‘prognostic marker’’ is defined according to REMARK Guidelines [ | PMC10318767 |
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Data collection | death, CRC, ALRI, AJCC, Cancer | METASTASIS, RECURRENCE, PRIMARY TUMOR, BLOOD, CANCER | Patients’ demographic and clinicopathological features were obtained from retrospective medical records. The pathological staging of patients was defined using both the traditional TNM staging and the American Joint Committee on Cancer (AJCC) staging, respectively. Data on lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, platelet, lymphocyte, and neutrophil were extracted from the results of the first blood routine tests and biochemical tests (limit to 30 days prior to surgery). Blood routine tests and biochemical tests were based on a single blood sample of each patient and were measured by auto analyzers.The De Ritis ratio, aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase-to-lymphocyte ratio index (ALRI), aspartate aminotransferase-to-neutrophil ratio index (ANRI), and alkaline phosphatase-to-platelet ratio index (APPRI) were calculated using the following formulas: De Ritis ratio = aspartate aminotransferase level (U/L)/alanine aminotransferase level (U/L) [Patients were followed up regularly according to NCCN guidelines. The last time of follow-up was January 22, 2019. The survival information was obtained from contacts with patients by phone. Overall survival (OS) was defined as the period from surgery to death from any cause, or the last contact. Disease-free survival (DFS) was defined as the period from surgery to local recurrence, distant metastasis, a new primary tumor of CRC, or death, whichever comes first. | PMC10318767 |
Statistical analysis | tumor, CRC | TUMOR | Multiple imputation was conducted to fill the missing data of the included variables [The 1-, 3-, and 5-year OS and DFS were calculated using the Kaplan–Meier method, and the survival differences of CRC patients between low and high levels of serum liver enzymes were compared using log-rank tests. The prognostic values of clinicopathological features and preoperative serum liver enzyme markers were estimated using univariate and multivariate Cox proportional hazards models, and the results were presented as hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were also conducted stratified by age, gender, tumor location, tumor diameter, CEA, and CA19-9.The nomograms that combined significant serum liver enzyme markers and clinicopathological features were developed, to predict the probability of 1-, 3- and 5-year survival recurrence/metastasis of patients with stage II/III CRC in the training and testing sets. The variables with a The prediction accuracy of nomograms was evaluated by the concordance index (C-index) [All the statistical analyses were conducted with SPSS 24.0 (SPSS Inc., Chicago, IL, USA) and R 4.1.2 software (Institute for Statistics and Mathematics, Vienna, Austria). Two-sided | PMC10318767 |