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Analysis | Descriptive statistics were used to describe participant characteristics. All quantitative data analyses were performed using SPSS Version 25 (IBM Corp., Armonk, NY, USA). All qualitative data were audio-recorded and transcribed verbatim by MvT. Using data from the first focus group, first three of nine patient and first three of eight physiotherapist interviews, MvT and CK independently identified codes, grouped them into meaningful categories and subsequently categorized them into main themes using ATLAS.ti 9 for Windows. Codes and main themes from these interviews were discussed between MvT and CK until consensus was reached. After the consensus meeting, MvT independently analyzed the rest of the interviews and focus groups. Transcripts and findings were not returned to participants for comments or corrections and field notes were not made, because data were felt to be straightforward and unlikely to be misinterpreted. | PMC9996840 | ||
Results | PMC9996840 | |||
Phase 1 - development of matched treatment options | Three focus groups were conducted with physiotherapists and physiotherapy experts. Focus group participant characteristics can be found in Table
Focus group participant characteristicsWork background, 5 (100)1 (20)0 (0)1 (20)0 (0)5 (100)1 (20)(0)1 (20)(0)7 (100)4 (57)1 (14)4 (57)2 (29)*Columns add to percentages that exceed 100%, because participants might have multiple work backgroundsMain themes and related codes are described below. A visual representation of the developed Stratified Blended Physiotherapy approach, including the developed matched treatments, is presented in Table | PMC9996840 | ||
Developed version of the stratified blended physiotherapy approach, including matched treatments | pain | A visual representation of the developed Stratified Blended Physiotherapy approach, including the matched treatments, is presented in Table
Overview of the Stratified Blended Physiotherapy approach, developed in phase 1 of this study
Is to be matched to the patient’s risk of persistent disabling pain (low, medium or high, assessed with the Keele STarT MSK Tool)
Is to be matched to the patient’s suitability for blended care (yes or no, assessed with the Dutch Blended Physiotherapy Checklist by the physiotherapist) | PMC9996840 | |
Phase 2 - findings of the feasibility study | Eight physiotherapists invited 23 eligible patients. Of these patients, 13 signed informed consent forms and were enrolled in the study and the rest declined to participate after reading the information letter. Eight physiotherapists and 13 patients completed the follow-up questionnaire. No patients were lost to follow-up and two physiotherapists were lost to follow-up due to self-reported lack of experience with the Stratified Blended Physiotherapy approach and therefore were not willing to participate in the follow-up data collection. Physiotherapist and patient characteristics are presented in Tables
Feasibility study physiotherapist characteristicsSpecialization, 5 (63)3 (37)Experience with blended or stratified physiotherapy, 4 (50)2 (25)0 (0)2 (25)
Feasibility study patient characteristicsRisk subgroup (STarT MSK Tool), 8 (61)4 (31)1 (8)5 (56)3 (33)1 (11) | PMC9996840 | ||
Phase 2 - quantitative results | ’ | Physiotherapists’ satisfaction with delivery of the new approach was scored as ‘a little satisfied’ (median = 3; IQR = 1; n = 8). Physiotherapists’ experienced usability of the physiotherapist web based dashboard of the app was 40 (median; IQR = 9.4; n = 8), which is considered as ‘OK’ usability [Patients’ rating of global improvement at the end of treatment was scored as ‘a little improved’ (median = 3; IQR = 2; n = 13). Patients’ satisfaction with treatment was scored as ‘a little satisfied’ (median = 3; IQR = 2; n = 13). Patients’ willingness to recommend the app was 9 (median; IQR = 4; n = 11). No patients received the paper-based workbook, because there were no patients considered unsuitable for e-Exercise by physiotherapists. Patients’ experienced usability of the developed app was 87.5 (median; IQR = 30; n = 11), which is considered as ‘best imaginable’ usability. | PMC9996840 | |
Phase 2 - qualitative results | All 8 physiotherapists and 9 of the 13 invited patients who completed the follow-up questionnaires were interviewed. Four patients did not want to participate in an interview. Results were structured according to the main themes. | PMC9996840 | ||
Discussion | e-Exercise LBP, MSK complaints, neck/shoulder pain, pain | In the first phase of this study, matched treatment options were developed for six subgroups as part of the Stratified Blended Physiotherapy approach for patients with neck and/or shoulder complaints. Recommendations about the content and intensity of physiotherapy treatment were matched to the patient’s risk of persistent disabling pain (using the Keele STarT MSK Tool; low, medium, or high risk), and mode of physiotherapy delivery was intended to be matched to the patient’s suitability for blended care (using the Dutch Blended Physiotherapy Checklist (i.e. yes or no). A paper-based workbook and the e-Exercise app modules for patients with neck and/or shoulder complaints were developed as practical tools for the mode of delivery matched treatment options. In the second phase of this study, feasibility of the developed Stratified Blended Physiotherapy approach for patients with neck and/or shoulder complaints was investigated for both patients and physiotherapists. Patients and physiotherapists were ‘a little’ satisfied with the new approach. Of the patients who were willing to participate, they considered the e-Exercise app as ‘best imaginable’ usability. Usability of the physiotherapist dashboard to set up the e-Exercise app was considered ‘OK’ by physiotherapists. This can be largely explained by the lack of a cockpit functionality with an overview of active patients and their progress and a lack of a logical workflow. The paper-based workbook was not used, so there is no data of patients that were unsuitable for blended care. Results of the second phase can be used to develop, improve or implement e-Exercise or other blended interventions.This is the first study to develop and test feasibility of integrated risk stratification and blended care in patients with neck and/or shoulder complaints. Also, no stratification tools to identify patient subgroups and subsequently match them to a treatment are recommended by Dutch physiotherapy guidelines for neck/shoulder pain [In this study, we identified some improvements needed to be made to the Stratified Blended Physiotherapy approach before initiating a cluster randomized trial to determine the clinical effectiveness of the new approach compared to usual physiotherapy. First, patients needed an overview of the steps and possibilities of the e-Exercise app module. Therefore, an instruction sheet called ‘working with the e-Exercise program through MijnZorgApp’ was developed for patients. Second, physiotherapists needed a cockpit functionality in the physiotherapist dashboard of the app module with an overview of active patients and their progress. Therefore, a cockpit functionality was developed for physiotherapists to see which action is needed for which active patient, with the aim to provide a more logical workflow. Third, improvements need to be made to the physical activity module of the app. It is suggested to integrate an activity tracker or personal health environment with the app. The integration of an activity tracking device with a display was also suggested in a previously executed feasibility study on e-Exercise [A strength of this study was the use of knowledge from a previously developed and evaluated stratified blended intervention for patients with other MSK complaints, namely non-specific low back pain (e-Exercise LBP), in which patients and physiotherapists were involved in the participative development, and was conducted by the same research group [Despite the careful execution of this study, there are some methodological considerations. The digital questionnaire was sent three months after the first physiotherapy session. This is a relatively long time gap, especially for patients at low risk, which might have led to recall bias. However, we chose follow-up at 3 months to ensure that all participants would have been able to receive their matched intervention, and to ensure the follow-up time-point was the same for all subgroups. Also, because of the small number of included patients, physiotherapists did not gain the experience to fully familiarize the Stratified Blended Physiotherapy approach. Therefore, there were no physiotherapists which made the Stratified Blended Physiotherapy approach part of their daily work routine, which might have influenced feasibility outcomes. Experiences might have been different in that theoretical group, because behavior change of the physiotherapist will need time and experience. Additionally, no a priori sample size calculations were done. The small sample of physiotherapists and patients, and the fact that only one patient at high risk was included in the feasibility analyses might have led to limited generalizability. Therefore, in the subsequent cluster randomized trial, continuous actions will be taken to maximize inclusion rates. | PMC9996840 | |
Conclusion | In conclusion, this study described the participative intervention development and feasibility testing of physiotherapy delivered matched treatment options as part of the Stratified Blended Physiotherapy approach for patients with neck and/or shoulder complaints. To serve a diverse group of patients, both app-based as well as paper-based materials were developed. However, the paper-based workbook was not used in the feasibility study. The results have informed amendments to the Stratified Blended Physiotherapy approach for patients with neck and/or shoulder complaints ready to use within a future cluster randomized trial. | PMC9996840 | ||
Acknowledgements | Not applicable. | PMC9996840 | ||
Authors’ contributions | All authors (MLvT, CJJK, MFP, JBS, NEF, RWJGO and CV) made substantial contributions to the design of this study, have drafted the work or substantively revised it. Furthermore, all authors (MLvT, CJJK, MFP, JBS, NEF, RWJGO and CV) read and approved the final version of this manuscript. Finally, all authors (MLvT, CJJK, MFP, JBS, NEF, RWJGO and CV) agree both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. | PMC9996840 | ||
Funding | This work was supported by the Scientific College Physical Therapy (WCF) of the Royal Dutch Society for Physical Therapy (KNGF). | PMC9996840 | ||
Data availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. | PMC9996840 | ||
Declarations | PMC9996840 | |||
Ethics approval and consent to participate | Because the interventions used in the treatment are the same as reported in physiotherapeutic guidelines, and only the treatment delivery differs, the Medical Ethical Committee of the HU University of Applied Sciences declared that this study was not covered by the Dutch Medical Research Involving Human Subject Act (WMO) and therefore did not require medical ethical approval, with reference number: 81_000_2018. Written informed consent was obtained from all participating patients. All physiotherapists gave verbal consent to use their data pseudonymously. The Medical Ethical Committee of the HU University of Applied Sciences approved the informed consent procedure, with reference number: 81_000_2018. All methods were carried out in accordance with relevant guidelines and regulations. | PMC9996840 | ||
Consent for publication | Not applicable. | PMC9996840 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9996840 | ||
List of abbreviations | MusculoskeletalSubgroup targeted treatmentUnited KingdomGlobal Perceived Effect – Dutch VersionNet Promoter ScoreSystem Usability ScaleElectronic health recordLow back pain | PMC9996840 | ||
References | PMC9996840 | |||
Purpose | diabetic vitrectomy | EYE, LOW VISION | Edited by: Ravirajsinh Jadeja, Augusta University, United StatesReviewed by: Alexander E. Berezin, Zaporizhia State Medical University, Ukraine; Meirong Chen, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, China; Du Liping, Chongqing Eye Institute, China†These authors have contributed equally to this work‡ORCID: Bojie Hu, We aimed to evaluate the risk factors and develop a prognostic nomogram of long-term low vision after diabetic vitrectomy. | PMC10485701 |
Methods | low vision | REGRESSION, NONPROLIFERATIVE DIABETIC RETINOPATHY, LOW VISION | This retrospective study included 186 patients (250 eyes) that underwent primary vitrectomy for proliferative diabetic retinopathy with a minimum follow-up period of one year. Patients were assigned to the training cohort (200 eyes) or validation cohort (50 eyes) at a 4:1 ratio randomly. Based on a cutoff value of 0.3 in best-corrected visual acuity (BCVA) measurement, the training cohort was separated into groups with or without low vision. Univariate and multivariate logistic regression analyses were performed on preoperative systemic and ocular characteristics to develop a risk prediction model and nomogram. The calibration curve and the area under the receiver operating characteristic curves (AUC) were used to evaluate the calibration and discrimination of the model. The nomogram was internally validated using the bootstrapping method, and it was further verified in an external cohort. | PMC10485701 |
Results | tractional retinal detachment, hypertension | REGRESSION, TRACTIONAL RETINAL DETACHMENT, HYPERTENSION | Four independent risk factors were selected by stepwise forward regression, including tractional retinal detachment (β=1.443, OR=4.235, P<0.001), symptom duration ≥6 months (β=0.954, OR=2.595, P=0.004), preoperative BCVA measurement (β=0.540, OR=1.716, P=0.033), and hypertension (β=0.645, OR=1.905, P=0.044). AUC values of 0.764 (95% CI: 0.699-0.829) in the training cohort and 0.755 (95% CI: 0.619-0.891) in the validation cohort indicated the good predictive ability of the model. | PMC10485701 |
Conclusion | diabetic vitrectomy | LOW VISION | The prognostic nomogram established in this study is useful for predicting long-term low vision after diabetic vitrectomy. | PMC10485701 |
Introduction | PDR, TRD, Diabetic retinopathy, blindness, tractional retinal detachment, postoperative vision, vitreous hemorrhage | TRACTIONAL RETINAL DETACHMENT, DIABETIC RETINOPATHY, BLINDNESS, VITREOUS HEMORRHAGE, COMPLICATIONS | Diabetic retinopathy (DR) has become the leading cause of blindness among working-age adults (20–79 years old) (The development of microincision vitrectomy surgery has greatly improved the precision, safety, and efficiency of intraocular surgery in recent years. Pars plana vitrectomy (PPV) has been widely used in the treatment of PDR complications, including un-clearing vitreous hemorrhage (VH) (1–6 months) and tractional retinal detachment (TRD) involving or threatening the macula (Before surgery, a better understanding of prognostic factors related to long-term vision after vitrectomy can help clinicians make better surgical decisions, assist patients with PDR in adjusting their psychological expectations, and foster better patient-doctor communication. Previous studies have explored several factors related to postoperative vision; however, the independent variables differ among them ( | PMC10485701 |
Methods | PMC10485701 | |||
Study design and participants | PDR | EYE | This is a single-center and retrospective study (registered at ClinicalTrials.gov: NCT05631054). It was approved by the Ethics Committee of Tianjin Medical University Eye Hospital (approval number: 2022KY-27) and was conducted in accordance with the Declaration of Helsinki. We included 186 PDR patients (250 eyes) who underwent primary vitrectomy in Tianjin Medical University Eye Hospital from January 2016 to October 2021. We defined 12 months postoperatively as a long-term period because previous studies have indicated that patients could gain stable visual acuity after this period of time ( | PMC10485701 |
Surgical procedures | cataracts, tamponade | RETINA, ADHESION, LENS, PROLIFERATIVE, CATARACTS, CORTEX | Standard 23- or 25-gauge PPV was performed under retrobulbar anesthesia. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs was performed 3–5 days prior to surgery in eyes with broad basement adhesion of the fibrovascular proliferative membrane to the retina. The anterior, posterior, and peripheral vitreous body were substantially removed using a high-speed vitrectomy surgical system, and the posterior vitreous cortex was removed with the aid of triamcinolone acetonide. Moreover, neovascular membranes were dissected and/or peeled off. Endo-laser photocoagulation was finished, and the number of laser shots depended on the preoperative laser status and detached area of the retina. Depending on the condition of the retina, tamponade with a balanced salt solution, air, C3F8 gas, or silicone oil was used. Intravitreal injection of anti-VEGF drugs or dexamethasone intravitreal implant was performed, if necessary. Phacoemulsification and intraocular lens implantation were combined for visually significant cataracts. Generally, silicone oil was removed 3–6 months postoperatively when the retina was stable. The surgical procedures were all performed by one surgeon. | PMC10485701 |
Data collection | TRD, tractional retinal detachment, diabetes | TRACTIONAL RETINAL DETACHMENT, CORONARY HEART DISEASE, HYPERTENSION, CEREBRAL INFARCTION, DIABETES | We collected data by reviewing the patients’ medical records. As systemic factors, we collected the information on sex, age, diabetes type, diabetes duration, hypertension, dialysis, coronary heart disease, cerebral infarction, and blood test (the details are listed in Baseline characteristics of the training cohort.a: chi-squared test, b: Mann-Whitney test, c: t-test; HbA1c, glycosylated hemoglobin A1c; CHD, coronary heart disease; TC, total cholesterol; TG, triglyceride; PT, prothrombin time.APTT, activated partial thromboplastin time; FIB, fibrinogen; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate.HGB, hemoglobin; TRD, tractional retinal detachment; PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor. | PMC10485701 |
Statistical analysis | diabetic vitrectomy, Low vision | REGRESSION, LOW VISION, LOW VISION | Low vision was defined as a BCVA<0.3, according to the standard of the WHO 2015 (The multivariate binary logistic regression analysis considered variables with a P-value<0.1 from the univariate analysis, and stepwise forward regression was used to explore variables with a P-value<0.05 as potential independent predictors. The variance inflation factor was calculated to test for multicollinearity amongst the independent variables. In accordance with the outcomes of the multivariate logistic regression analysis, a nomogram for estimating the probability of long-term low vision after diabetic vitrectomy was built.The discrimination capacities of the predictive indicators were described using receiver operating characteristic (ROC) curves. Generally, a value >0.7 of the area under the ROC curve (AUC) is considered to indicate good discrimination. The threshold of the equation was determined by the maximum Youden Index (sensitivity + specificity - 1). The calibration was tested and depicted using the Hosmer-Lemeshow test and calibration curves. The nomogram was internally validated using the bootstrapping approach, and it was externally validated in an external cohort. All statistics were analyzed using IBM SPSS Statistics ver. 25.0 (SPSS, Chicago, IL, USA) and R software ver. 4.0.1 (R Project for Statistical Computing, Vienna, Austria). A two-sided P-value of<0.05 was considered statistically significant. | PMC10485701 |
Results | PMC10485701 | |||
Patient characteristics and ophthalmic outcomes | PDR, NVG, retinal detachment | EYE, RETINAL DETACHMENT, LOW VISION | A total of 491 patients underwent primary vitrectomy for PDR at Tianjin Medical University Eye Hospital from January 2016 to October 2021. Among them, 186 patients (250 eyes) who met the eligibility criteria were included in this study. The mean follow-up duration was 32 ± 21 months. For all eyes, the mean postoperative BCVA was 1.53 ± 0.66 logMAR, and it increased to 0.8 ± 0.85 logMAR at the last follow-up (P<0.001). The total incidence of long-term low vision was 43.6%. The rate of improvement, invariant, and worsening of BCVA was 68.8%, 15.2%, and 16.0%, respectively. The rate of the final BCVA of ≥0.7, 0.3–0.7, 0.1–0.3, and<0.1 was 22%, 34.4%, 18.4%, and 25.2%, respectively. Final anatomical success was achieved in 235 eyes (94%). During the follow-up period, 40 eyes (16%) underwent re-vitrectomy for recurrent VH in 31 eyes and retinal detachment in 9 eyes, and 18 eyes (7.2%) developed NVG. | PMC10485701 |
Predictive model and nomogram development | TRD, diabetic vitrectomy, tractional retinal detatchment, low vision | REGRESSION, LOW VISION | In the training cohort of 200 eyes, low vision occurred in 89 eyes (44.5%). Considering the practical clinical application, we stratified three continuous variables: age (≤55 years old, >55 years old), symptom duration (<6 months, ≥6 months), and eGFR (<60 mL/min/1.73 mStepwise multivariate logistic regression for long-term low vision after diabetic vitrectomy.TRD, tractional retinal detatchment; m, months; where The variance inflation factor of each predictor in this model was<10, indicating there was no multicollinearity among the independent variables. The cutoff score that maximized the Youden index was 0.495 (sensitivity, 62.9%; specificity, 78.4%).Then a nomogram was depicted to present the logistic prediction model (Nomogram for predicting long-term low vision after diabetic vitrectomy. | PMC10485701 |
Validation and evaluation of the nomogram | TRD, tractional retinal detachment | REGRESSION, CORONARY HEART DISEASE, TRACTIONAL RETINAL DETACHMENT | The ROC curves for the model and each predictor are depicted in ROC curves of multivate logistic regression model.Calibration curve of the risk prediction model.Comparison of baseline characteristics of training cohort and validation cohort.a:chi-squared test, b: Mann-Whitney test, c: t-test; HbA1c, glycosylated hemoglobin A1c; CHD, coronary heart disease; TC, total cholesterol; TG, triglyceride; PT, prothrombin time.APTT, activated partial thromboplastin time; FIB, fibrinogen; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate.HGB, hemoglobin; TRD, tractional retinal detachment; PRP, panretinal photocoagulation; VEGF, vascular endothelial growth factor. | PMC10485701 |
Renal function-stratified analysis | non-low vision, NVG, renal insufficiency | REGRESSION, HYPERTENSION, RENAL INSUFFICIENCY | In the training cohort, eGFR differed significantly only in the univariate analysis between the low and non-low vision groups. We further analyzed the features and prognosis of all the patients with borderline/normal renal function (n=184), early renal insufficiency (n=43), and poor renal function (n=23). For baseline characteristics, patients with worse renal function were shown to have significantly longer symptom duration, more hypertension, lower hemoglobin levels, lower hemoglobin A1c levels, and higher fibrinogen levels (P<0.05). There was no significant difference in preoperative median BCVA measurement (normal eGFR group, 1.7 (1.0–2.0) logMAR; median eGFR group, 1.5 (1.0–2.3) logMAR; low eGFR group, 2.3 (0.8–2.3) logMAR; P=0.178). The long-term BCVA significantly improved in the three groups (P<0.01); however, those with lower eGFR experienced considerably worse vision outcomes (normal eGFR group, 0.4 (0.15–1.0) logMAR; median eGFR group, 0.7 (0.4–1.3) logMAR; low eGFR group, 0.8 (0.4–2.3) logMAR; P=0.011). Furthermore, there was no significant difference in BCVA changes among the groups (P=0.068). After adjusting for symptom duration and hypertension, renal function was still an independent predictor of negative visual outcomes in the multilinear regression analysis (P=0.024). The incidence of NVG in the renal insufficiency group (n=66) was substantially higher than that in the group of patients with borderline/normal renal function (13.6% vs. 4.9%, P=0.018). Finally, incidence of re-vitrectomy in the three groups did not differ significantly from one another (P=0.933). | PMC10485701 |
Discussion | PDR, TRD, death, CKD, postoperative recurrent detachment, diabetic vitrectomy, kidney failure, NVG, hypertension, diabetes | MICROINVASIVE, LOW VISION, KIDNEY FAILURE, HYPERTENSION, COMPLICATIONS, DIABETES | For serious PDR complications, vitrectomy may be the only approach to improve visual acuity. Microinvasive vitreous surgery and an optimized vitrectomy platform with fluid and pressure control have greatly reduced the complications of PPV; however, some patients cannot fully achieve their ideal visual function long-term after diabetic vitrectomy. The estimated incidences of long-term postoperative BCVA<0.3 and<0.1 are 40% and 20%, respectively (In this study, TRD, symptom duration, preoperative BCVA measurement, and hypertension were identified as independent risk factors for long-term low vision after diabetic vitrectomy. With an AUC value of 0.764, along with 0.747 and 0.755 in the internal and external validation cohorts, the risk prediction model based on the four parameters demonstrated good discrimination. The nomogram provided a graphical representation of mathematical formulas, facilitating understanding and application. The factors in this model are easily obtainable, allowing doctors to make a preliminary evaluation of long-term functional outcomes through routine examinations and have good preoperative communication with patients.In this model, TRD involving or threatening the macular was regarded as the greatest risk factor. Patients with TRD had a 4.235 times increased incidence of postoperative long-term low vision than individuals without TRD. Although the final retinal reattachment rates have been reported to range from 95–100% (In addition to the four independent risk factors identified in this study, other factors have also been thought to affect visual acuity after diabetic vitrectomy. The progression of PDR is thought to be considerably influenced by the age at diabetes onset. Younger patients usually present with more severe anatomical features and have a higher rate of NVG and postoperative recurrent detachment (CKD is also a concern for researchers; for instance, kidney failure was regarded as the most frequent cause of death in patients who underwent diabetic vitrectomy (Although previous studies have explored the prognostic factors of long-term visual acuity after diabetic vitrectomy (Postoperative long-term visual acuity is the most concerning issue for patients with PDR. In this study, a BCVA measurement of 0.3 was selected as the cutoff value according to the WHO 2015 standard. In clinical practice, we also found a BCVA measurement of 0.3 to be the critical value of subjective feeling for patients with PDR. Additionally, in this study, the surgical procedures were performed by one surgeon, eliminating the impact of skill level and treatment habits on the prognosis.Nevertheless, this study had some limitations. First, confounding variables and bias are present owing to its retrospective nature. Second, we could not obtain comprehensive preoperative and follow-up data. Finally, this study did not consider the difference between 23-gauge and 25-gauge vitrectomy systems because previous studies have proved that the differences of these systems in terms of visual prognosis are negligible (In conclusion, TRD, symptom duration, preoperative BCVA measurement, and hypertension are independent risk factors of long-term low vision after diabetic vitrectomy. The risk prediction model based on these four risk factors exhibited good predictive value. This prognostic nomogram could help clinicians make better surgical decisions, assist patients with PDR in adjusting their psychological expectations, and foster better patient-doctor communication. | PMC10485701 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10485701 | ||
Ethics statement | EYE | The studies involving human participants were reviewed and approved by Ethics Committee of Tianjin Medical University Eye Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. | PMC10485701 | |
Author contributions | WL | BH, HG, ZW, and XL designed the study. HG and ZW wrote the manuscript. Data collection was performed by HG, ZW, ZN, XZ, KW, ND, SB, and WL. HG and ZW completed all statistical analysis. All authors contributed to the article and approved the submitted version. | PMC10485701 | |
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10485701 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10485701 | ||
References | PMC10485701 | |||
2. Materials and Methods | PMC9967049 | |||
2.1. Study Design | adenoid hypertrophy, OME | TYMPANIC MEMBRANE RETRACTION, POLAND, ADVERSE EFFECTS, ADENOID HYPERTROPHY, MIDDLE EAR, ACUTE OTITIS MEDIA, NECK DISEASE | We conducted a pilot, single-arm trial. Our study population comprised 36 patients recruited from the Outpatient Clinic of the Department of Otorhinolaryngology, Head and Neck Diseases in Olsztyn, Poland. All patients provided written informed consent. Patients were included if they filled the following criteria:Otologic diagnosis of unilateral or bilateral OME in the otoscopy at the visit before the recruitment;At least unilateral type B, C1, or C2 tympanogram;Aged between 18 and 70 years.The exclusion criteria were:Otologic diagnosis of acute otitis media and other ear abnormalities at the visit before the recruitment;History of the active neoplastic disease;Current pregnancy;History of adenoid hypertrophy or nasal polyps.Ethical approval was obtained from the ethics committee of the University of Warmia and Mazury (reference number 16/2017). All participants gave written informed consent.Baseline characteristics of patients (age, gender, date of initial outpatient clinic visit), as well as prior medical history, were extracted from the electronic patient dataset. We collected data on adverse effects occurring during the administration of the treatment using a standard questionnaire. Nasal endoscopy was made by board-certified otolaryngologists with at least 15 years of experience. Tympanometry and otoscopy findings were recorded before and after the intervention. A normal tympanic membrane was diagnosed when no gas bubbles, exudate, or retraction were present. A pathological eardrum was identified when bubbles, middle ear exudate, or tympanic membrane retraction were noted. The intervention structure and procedures are shown in | PMC9967049 |
2.2. Intervention | The study intervention consisted of 3 days of inhalation (2 inhalations at each visit) with an AMSA device (ATOMISORAn atomizer, with a capacity of 12 mL, is a hand-held device fitted with a binary nasal adapter. It produces from an aerosol fluid with a particle size of 2.2 µm, emitted at a flow rate of 0.20 mL per minute [For the first inhalation, the aerosol was obtained from a solution composed of: 2.5 mL of ambroxol solution for nebulization (7.5 mg/mL) mixed with 1 mL of 0.9% saline. The second inhalation’s aerosol consisted of a suspension of 2 mL budesonide (0.25 mg/mL) mixed with 1 mL of 0.9% saline. In total, patients received 1.5 mg of budesonide and 56.25 mg of ambroxol by nebulization during three days of treatment. | PMC9967049 | ||
2.3. Tympanometry | OME | Tympanometry was performed before and on after the intervention (the third day of the inhalation). Tympanograms were obtained using the Interacoustics Titan Clinical device and Titan Suite Software (Interacoustics A/S, Middelfart, Denmark). We measured the following parameters: volume (normal range: <2.5 mL), compliance (normal range: 0.3–1.5 mL), pressure (normal range: [-]100–100 daPa), gradient (normal range: <150 daPa), tympanogram type (Jerger’s classification: A, B, C1, C2).Tympanograms B and C2 were interpreted as OME. Tympanogram C1 was interpreted as a regurgitation of the ET. Normalization was defined as a conversion from B/C1/C2 to A and B/C2 to C1 tympanogram. A transition from B to C2 was interpreted as improvement, and a transition from C1/C2 to B or from A to B/C1/C2 was interpreted as deterioration. The persistence of the same tympanogram type was interpreted as no change. The patients with normalization and improvement were considered responders, while those with no change or deterioration were considered non-responders. | PMC9967049 | |
2.4. Statistical Analysis | We described patients’ baseline characteristics using a median and interquartile range for continuous and percentages for categorical variables. First, at the participant level, we described a proportion of patients achieving response to AMSA treatment stratified by completeness and laterality. Then, the tympanometry data were analyzed using the affected ear as a unit of analysis (not individual patients—ear-level analysis). Such an approach was adopted in several previous studies [We used two-sided | PMC9967049 | ||
3. Results | ADVERSE EVENTS, MIDDLE EAR | The baseline characteristics of study participants is summarized in All patients completed the intervention and participated in the follow-up visit. No major adverse events were reported.At the patient level (We observed a significant difference in the distribution of tympanogram types following the intervention (Analyses for continuous parameters showed an increase in the volume of the middle ear (∆None of the proposed effect modifiers (age, sex, and season) had a statistically significant effect on treatment efficacy (all | PMC9967049 | |
4. Discussion | OME | MIDDLE EAR, PATHOLOGY, PATHOGENESIS | To the best of our knowledge, this study is the first trial of inhaled mucolytics and steroids in adults with OME, in whom tympanometry was assessed at baseline and after treatment. We found high rates of improvement in tympanometry after three days of treatment. Following AMSA administration, we observed significant improvement in volume, pressure, and compliance measured in tympanometry. No significant differences in response to treatment were observed for patients’ age, sex, or season of inclusion.A short course of AMSA with a nebulized mucolytic drug and steroid in OME could be regarded as an effective treatment alternative. Moreover, it avoids more disruptive and costly interventions such as myringotomy and grommet insertion. Previous research showed some evidence in favor of AMSA use for OME treatment in children under the age of 18 years. The characteristics and results of previously published studies using AMSA are summarized in These studies vary in the duration of treatment, medication, and outcome assessment methods. In contrast to the other studies that included children, as noted previously, our focus is on the adult population. While the length of intervention in previous studies was at least 5 days, our study demonstrated that a three-day course may also result in a clinical benefit. The reduced duration of treatment was possible due to the adults’ facilitated cooperation and more comprehensive implementation of instructions as compared to the children. Each of the previous studies used a different medication protocol—mucolytics alone [The drugs applied in AMSA are generally steroids combined with a mucolytic drug, saline, or an antibiotic. Locally applied steroids via pulsatile airflow have been shown to facilitate ventilation efficiency and ensure appropriate medication distribution to hard-to-reach areas [Studies adopting Politzer insufflations or nasal lavage can be a source of concepts for new AMSA drug protocols. Mirandola et al. reported a clinical improvement of OME in children after Politzer insufflations of sulphurous water, which they compared to the untreated control group [No single perfect method for evaluating the state of the middle ear currently exists. Most studies use pure tone audiometry [The condition of the ET has been linked to OME pathogenesis [Our study is not free of limitations. First, this study did not involve a control group. Secondly, the study sample was relatively small, but its pilot character explains this. Patients did not receive a disease-specific quality-of-life questionnaire, nor undergo imaging to exclude nasopharyngeal or anterior/middle cranial fossa pathology, possibly impairing ET function. No pure tone audiometry nor another hearing test before and after the intervention were performed. Moreover, we did not consider a long-term follow-up visit after the end of the intervention. Clearly, larger, controlled clinical studies need to be conducted to confirm our results.An undoubtful strength of this study is that it is the first report of AMSA use in OME management in adults. Observed effect sizes can be further utilized in the calculation of a minimum sample size in future studies. | PMC9967049 |
5. Conclusions | OME | MIDDLE EAR, REMISSION | A 3-day course of mucolytics and steroid administration with AMSA was reported to be relatively effective for symptom withdrawal in adults with OME. Partial and complete OME remission was noted in, respectively, 81% and 39% of patients. Moreover, an increase in volume and pressure in the middle ear were observed following the treatment. Treatment efficacy did not depend on patients’ age, sex, or the season of inclusion in the trial. The results of this pilot study are encouraging; however, the use of AMSA management of OME in adults needs to be verified in future studies. | PMC9967049 |
Author Contributions | Conceptualization, K.Z.-S. and N.J.-A.; methodology, K.Z.-S. and N.J.-A.; software, B.K.; validation, K.Z.-S. and B.K.; formal analysis, K.Z.-S.; investigation, K.Z.-S., B.K. and N.J.-A.; resources, K.Z.-S.; data curation, B.K.; writing—original draft preparation, K.Z.-S.; writing—review and editing, K.Z.-S.; visualization, K.Z.-S.; supervision, H.Z.; project administration, K.Z.-S. and N.J.-A.; funding acquisition, H.Z. All authors have read and agreed to the published version of the manuscript. | PMC9967049 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the University of Warmia and Mazury (reference number 16/2017, 25 April 2017). | PMC9967049 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9967049 | ||
Data Availability Statement | Data available on request due to restrictions, e.g., privacy or ethics. The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the protection of personal data. | PMC9967049 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9967049 | ||
Subject terms | gastric cancer | METASTASIS, SECONDARY, RECURRENCE, GASTRIC CANCER | Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy. | PMC10654517 |
Introduction | Gastric cancer, deaths | GASTRIC CANCER, RECURRENCE, COMPLICATIONS | Gastric cancer (GC) accounts for approximately 8% of cancer-related deaths worldwideNonetheless, lymphadenectomy is often merely performed based on the surgeon’s preference and experience. However, owing to the complex vascular anatomy and lymphatic drainage around the stomach, efficient and accurate dissection of LNs without increasing surgery-related complications remains a substantial challenge for surgeons, especially junior trained ones. Recently, with the successful application of indocyanine green (ICG) fluorescence imaging technology in minimally invasive surgeryRetrospective studiesIn this work, we present the subsequent follow-up results of FUGES-012, wherein the long-term oncologic outcomes of 3-year overall survival (OS), 3-year disease-free survival (DFS), and recurrence patterns are reported. | PMC10654517 |
Results | PMC10654517 | |||
Overall survival | deaths | The deaths of 52 patients resulted in a 3-year actual OS rate of 86.0% (18 of 129) in the ICG group and 73.6% (34 of 129) in the non-ICG group. The OS in the ICG group was statistically significantly better than that in the non-ICG group (log-rank | PMC10654517 | |
Disease-free survival | DFS | The DFS in the ICG group was statistically significantly better than that in the non-ICG group (log-rank In the ITT analysis, the survival analysis revealed that the DFS of the ICG group was better than that of the non-ICG group (log-rank | PMC10654517 | |
Recurrence | death | RECURRENCE | Within the first three years of follow-up, recurrence was found in 23 (cumulative incidence, 17.8%) and 40 (cumulative incidence, 31.0%) patients in the ICG and non-ICG groups, respectively (Table Treating death as the competing risk, a significant difference in the cumulative recurrence incidence was found between the ICG and non-ICG groups (HR = 0.54; 95% CI, 0.32–0.91; adjusted | PMC10654517 |
Incremental harvested lymph nodes in ICG group improve survival | REGRESSION | For pN0 patients, there is no statistically significant difference in prognosis between ICG and non-ICG patients (OS: Further analysis of patients with ≥30 retrieved LNs revealed that the OS in the ICG group was significantly higher than that in the non-ICG group (log-rank Multivariable Cox regression analysis (Supplementary Table | PMC10654517 | |
ICG reduces the LN dissection noncompliance and locoregional recurrence, and improves DFS | The LN dissection noncompliance rate in the ICG group (41 of 129 patients [31.8%]) was lower than that in the non-ICG group (74 of 129 patients [57.4%]; The OS of pN0 patients with compliant and noncompliant lymphadenectomy were comparable (log-rank Further analysis (Supplementary Fig. Among the full cohort, there are no significant interactive effects between ICG and LN dissection compliance on OS and DFS ( | PMC10654517 | ||
Discussion | tumor | REGRESSION, TUMOR, RECURRENCE, REFLUX, PRIMARY TUMOR | This RCT aimed to evaluate the role of ICG in LN tracing during laparoscopic radical gastrectomy. Our study shows that laparoscopic ICG fluorescence imaging-guided lymphadenectomy can improve the long-term OS and DFS of patients with GC and reduce the cumulative recurrence rate compared with conventional lymphadenectomy. This finding provides further evidence of the effectiveness and importance of ICG fluorescence imaging-guided lymphadenectomy in the treatment of GC.Previous studies have shown that within the specified scope of dissection, the greater the number of LNs retrieved, the better the long-term survival of GC patientsThis clinical trial found that the 3-year DFS rate and 3-year OS rates in the ICG group were significantly better than those in the non-ICG group, which may be due to more extensive and complete LN dissection in the ICG group. The pN stage of resectable GC is directly related to the number of metastatic LNsPrevious studies have shown that LN dissection noncompliance, especially major LN dissection noncompliance, significantly affects the long-term survival of GC patientsIt should be noted that the fluorescent LNs can only indicate, with an accuracy of about 62.2%–97.2%, that the LN receives lymphatic reflux from the tumor, though it is not necessarily a metastatic LN. Nevertheless, it is possible to have false negatives in ICG fluorescence, that is, nonfluorescent LNs with metastatic LNs as observed by near-infrared (NIR) imaging, with an incidence of 46.4% to 60%The recent therapeutic effectiveness of robot-assisted gastrectomy guided by ICG has been reportedICG solution was injected into the submucosal layer of the four quadrants around the primary tumor via endoscopy 1 day preoperatively. Patients who have previously undergone gastrectomy (such as distal gastrectomy) or endoscopic submucosal dissection may experience an alteration in their gastric wall anatomy, physiological function, and lymphatic drainageWith the reporting of previous studiesThe previously reported safety resultsThe present study had several limitations. First, this study only included patients from a single center. Based on the findings of this RCT, the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) group conducted a multicenter RCT (CLASS-11 trial; NCT04593615) to provide further evidence. Second, the study did not include patients receiving neoadjuvant therapy, and patients often had tumor and LN regression and fibrotic responses after neoadjuvant therapy, although previous studies have shown that ICG tracing can also improve the number of LNs retrieved in patients who received neoadjuvant chemotherapyIn conclusion, for patients with resectable GC, ICG fluorescence imaging-guided lymphadenectomy can not only significantly improve the total number of LNs retrieved in laparoscopic D2 radical gastrectomy for GC, but it also shows substantial long-term oncological efficacy compared with conventional lymphadenectomy. We suggest that ICG-guided laparoscopic radical lymphadenectomy for GC be routinely performed. | PMC10654517 |
Methods | PMC10654517 | |||
Study design | The current study was a phase 3, parallel, open-label RCT conducted at the Fujian Medical University Union Hospital (FMUUH), a tertiary referral teaching hospital in China. This clinical trial was registered at | PMC10654517 | ||
Participants | Cancer, AJCC, gastric adenocarcinoma | ONCOLOGY, CANCER, GASTRIC ADENOCARCINOMA | Patients were eligible to participate if they were aged 18 to 75 years, had an Eastern Cooperative Oncology Group (ECOG) score of 0 (asymptomatic) or 1 (symptomatic but completely ambulatory), and had histologically confirmed gastric adenocarcinoma diagnosed at the preoperative clinical stage of cT1 to cT4a, N0/ + , M0 according to the 7th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual | PMC10654517 |
Randomization and masking | tumor | TUMOR, RECRUITMENT, BLIND | Eligible patients were randomly assigned by a 1:1 ratio to either the ICG or non-ICG group. The data manager (M.L.), who was not involved in the eligibility assessment and recruitment of patients, performed randomization with a list of randomly ordered treatment identifiers generated by a permuted block design using SAS (version 9.2; SAS Institute Inc.). The allocation sequence was concealed from the surgeons who enrolled the patients until they were formally randomized to their groups. Informed consent was given to eligible patients two days before the operation. Either patients assigned to ICG or non-ICG groups, preoperative endoscopy is necessary for tumor location one day before the operation. The difference is that the ICG group received drug injections but the non-ICG group did not. Although it was not feasible to blind the surgeons and participants owing to the nature of the surgical clinical trial, the chemotherapy-treating oncologists were unaware of the intervention received by the patients. | PMC10654517 |
Procedures | tumor, Dehydration | TUMOR, DEHYDRATION, STERILE, BLIND, PRIMARY TUMOR, DEHYDRATION | In the ICG group, ICG was endoscopically injected around the tumor in patients one day before operation; 1.25 mg/mL ICG (Dandong Yichuang Pharmaceutical Co) was prepared in sterile water, and 0.5 mL of the solution was injected into the submucosal layer at four quadrants around the primary tumor, amounting to 2.5 mg of ICG. We used the PINPOINT Endoscopic Fluorescence Imaging System (NOVADAQ, Stryker, US) equipped with a fluorescence mode to obtain NIR fluorescent images in the ICG group. A simple finger-click can convert visible light into NIR images (infrared imaging, green fluorescence, and color-segmented fluorescence) without the need to change any equipment. Intraoperatively, the fluorescent mode was switched according to the situation (Supplementary Fig. All the operations were performed by two surgeons (C.-H.Z. and C.-M.H.) who are members of the same surgical team. All the participating surgeons in our study met the following criteria: they had performed more than 100 laparoscopic radical gastrectomies, completed a learning curve in laparoscopic radical LN dissection, passed the blind surgical video examination, and had ample experience in ICG-guided LN dissection for GC. The surgeons were unaware of the specific allocation of the patient before the start of surgery, to prevent any potential discrimination of surgical strategy.All pathological evaluations were performed in a standard manner. For the pathological evaluation protocol, we referred to the LNs containing isolated tumor cells, defined as single tumor cells or small clusters of cells ≤0.2 mm in greatest diameter, without stromal reaction, are classified as pN0 in GCInformation regarding hematoxylin-eosin staining of paraffin sections includes the following steps:(1) Tissue embedding. (1) ethanol dehydration: tissues are dehydrated gradually with ethanol solutions of different concentrations (70%, 80%, 90%, 95%, 100%, and 100%) for 40 min each. (2) clearing: the tissues are immersed in three xylene baths, 1 h for each bath. (3) impregnation: the tissues are immersed in three paraffin baths, 1 h for each bath. (4) embedding: liquid paraffin is poured into a mold box, and the tissue block that has been impregnated with paraffin is laid flat on the bottom. Notably, the cutting surface should be placed facing downwards. After the paraffin has solidified, the embedding frame is removed. Once the tissue block has cooled down and becomes completely hard, the excess paraffin around the tissue is trimmed and kept moderately to facilitate sectioning.(2) Section preparation: the pre-cooled wax block is fixed onto the microtome, ensuring that the section of the wax block is parallel to the blade, which is typically tilted at 15°. The wheel advance mechanism is rotated and slice thickness is adjusted to 4 μm to obtain evenly thick slices. A brush is held in the left hand and the microtome handle is rotated with the right hand to cut the slices. The slices are gently lifted with the brush and the excess wax is tweezed. The slices are placed face up in the water bath of the slide warmer, which is set at a temperature of approximately 45 °C. After flattening the slices, they are picked with forceps. The slices are attached to the glass slides by immersing one end of a slide vertically in the water and the forceps are used to push the slice two-thirds of the way onto the slide. After attaching the slices to the slides, they are left to air dry and then placed in a slide warmer at 65 °C for 1 h, followed by a 2-h baking process in an oven.Deparaffinization of paraffin-embedded tissue sections: the paraffin sections are embedded in xylene I for 10 min, followed by xylene II for 10 min, and xylene III for 10 min. Then, the sections are gradually deparaffinized in a series of solutions: anhydrous ethanol I for 5 min, anhydrous ethanol II for 5 min, 90% ethanol for 5 min, 80% ethanol for 5 min, 70% ethanol for 5 min, and finally 50% ethanol for 5 min.HE staining: the paraffin sections were stained with hematoxylin for 0.5–1 min, rinsed with tap water, differentiated in 1% hydrochloric acid alcohol for a few seconds, rinsed with tap water, blue with 1% ammonia water for 1 min, rinsed with running water for a few seconds, and counterstained with eosin for several seconds, followed by rinsing with running water.(5) Dehydration and mounting of slides: the paraffin sections were sequentially immersed in 75% ethanol for 2 min, 85% ethanol for 2 min, and then in absolute ethanol for 5 min twice. Subsequently, the sections were cleared in xylene for 5 min and mounted with neutral gum after being removed from the xylene bath.(6) Interpretation of results: the cell nucleus is blue, and the cytoplasm is red.The extent of gastric resection and D2 lymphadenectomy was determined according to the tumor location, as indicated in the Japanese guidelines | PMC10654517 |
Outcomes | death, desirableOS, upper gastrointestinal endoscopy, cancer, weight loss | RECURRENCE, CANCER, RECURRENCE | The primary original protocol endpoint (Supplementary Information The current AJCC Staging manual recommends that the removal of ≥30 regional LNs is desirableOS was defined as the time from surgery to death from any cause or the last follow-up, and DFS was defined as the time from surgery to recurrence or death from any cause or the last follow-up.A minimum follow-up period of 36 months was required for each patient after operation. Follow-up was conducted every 3 months for the first 2 years postoperatively, and every 6 months for the next 3 years.Most routine follow-up appointments included (1) physical examination and blood testing with carcinoembryonic antigen, cancer antigen 12-5, and cancer antigen 19-9 every 3 months for the first 2 years and every 6 months thereafter; (2) chest X-ray and abdominal computed tomographic scans every 6 months for 3 years; and (3) annual upper gastrointestinal endoscopy for 3 years. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was recommended if recurrence was suspected. Recurrence was identified based on medical history and physical examination in combination with imaging evaluation, cytology, or tissue biopsy (preferred when feasible). Otherwise, patients attended follow-up visits at shorter intervals than the planned schedule. Patients with specific symptoms, such as abdominal mass, weight loss, or obstruction that could develop concurrently with recurrence were evaluated, regardless of their follow-up schedule. | PMC10654517 |
Sample size | The main evaluation index in this study was the total number of retrieved LNs. Based on previous studies | PMC10654517 | ||
Statistical analysis | death | REGRESSION, SECONDARY, RECURRENCE, EVENT | There are no deviations in the analysis plan compared with the preregistered protocol. The per-protocol analysis set population was used for all analyses. ITT analysis was conducted for the primary end point and secondary survival points only. Continuous variables are expressed as mean (standard deviation (SD)), and categorical variables are expressed as numbers. The differences between the groups were assessed using the The 3-year DFS and OS rates were calculated using the Kaplan-Meier method, and the log-rank test was used to determine significance. The hazard ratios (HRs) comparing the ICG and non-ICG groups were estimated using Cox regression after confirmation of the proportional hazards assumption. Multivariable Cox regression analyses were performed to evaluate the effect of operation type on survival, after adjustment for clinicopathologic covariables that were significantly associated with the outcome in univariable analyses. Factors with a All-cause death was treated as a competing event for recurrence. The cumulative incidence in the presence of competing risks was calculated, and competing-risk survival regression was used as an alternative to Cox regressionAll data were analyzed using SPSS statistical software, version 22.0 (SPSS Inc), and the R software environment, version 4.2.0 (R Foundation for Statistical Computing). Statistical analysis was performed from July to October 2022. Supplementary Data | PMC10654517 |
Reporting summary | Further information on research design is available in the | PMC10654517 | ||
Supplementary information |
Supplementary InformationReporting SummaryPeer Review FileSupplementary Data 1Description of Additional Supplementary Files | PMC10654517 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-42712-6. | PMC10654517 | ||
Acknowledgements | We thank those who have devoted a lot to this study, including pathologists, further-study doctors, statisticians and nurses. Thanks for Dr. Zhi-Hong Huang, Public Technology Service Center, Fujian Medical University. Thank you to statisticians Liu Fengqiong and Chen Fa for their guidance in statistics. This study was supported by the Fujian Province Medical “Creating high-level hospitals, high-level medical centers, and key specialty projects (Min [2021] No.76), Talent Initiation Fund Project of Fujian Medical University Union Hospital (2022XH041), Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital (2022XH021). The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. | PMC10654517 | ||
Author contributions | C.Q.Y., Z.Q., H.C.M. and Z.C.H.: Concept and design. L.Z.Y., L.P., X.J.W., J.M.C., W.H.G. and L.G.T.: Acquisition, analysis, or interpretation of data. C.Q.Y., Z.Q., L.Z.Y., H.C.M. and Z.C.H.: Drafting of the manuscript. C.Q.Y., Z.Q., L.Z.Y., H.C.M. and Z.C.H.: Statistical analysis. Z.Q.L., W.J.B., L.J.X., L.J., C.L.L., L.M., T.R.H., H.Z.N., Z.G.R., H.X.B., W.H.G., L.Y.F. and X.K.X.: Administrative, technical, or material support. Z.Q. and C.Q.Y.: Supervision. | PMC10654517 | ||
Peer review | PMC10654517 | |||
Data availability | CM | The data supporting the findings in this study are available under controlled access due to data privacy laws related to patient consent for data. All the original clinical data will be made available on request from the corresponding author (Huang CM) at any time in a de-identified manner for research purposes only. The remaining data are available within the Article, Supplementary Information. Requests for data sharing will be managed in accordance with Fujian Medical University Union Hospital’s data access and sharing policy, which can be found in Supplementary Note | PMC10654517 | |
Competing interests | The authors declare no competing interests. | PMC10654517 | ||
References | PMC10654517 | |||
Background | REGRESSION | Two characteristics of commonly used outcomes in medical research are zero inflation and non-negative integers; examples include the number of hospital admissions or emergency department visits, where the majority of patients will have zero counts. Zero-inflated regression models were devised to analyze this type of data. However, the performance of zero-inflated regression models or the properties of data best suited for these analyses have not been thoroughly investigated. | PMC10523642 | |
Methods | REGRESSION | We conducted a simulation study to evaluate the performance of two generalized linear models, negative binomial and zero-inflated negative binomial, for analyzing zero-inflated count data. Simulation scenarios assumed a randomized controlled trial design and varied the true underlying distribution, sample size, and rate of zero inflation. We compared the models in terms of bias, mean squared error, and coverage. Additionally, we used logistic regression to determine which data properties are most important for predicting the best-fitting model. | PMC10523642 | |
Results | We first found that, regardless of the rate of zero inflation, there was little difference between the conventional negative binomial and its zero-inflated counterpart in terms of bias of the marginal treatment group coefficient. Second, even when the outcome was simulated from a zero-inflated distribution, a negative binomial model was favored above its ZI counterpart in terms of the Akaike Information Criterion. Third, the mean and skewness of the non-zero part of the data were stronger predictors of model preference than the percentage of zero counts. These results were not affected by the sample size, which ranged from 60 to 800. | PMC10523642 | ||
Conclusions | NB | REGRESSION | We recommend that the rate of zero inflation and overdispersion in the outcome should not be the sole and main justification for choosing zero-inflated regression models. Investigators should also consider other data characteristics when choosing a model for count data. In addition, if the performance of the NB and ZINB regression models is reasonably comparable even with ZI outcomes, we advocate the use of the NB regression model due to its clear and straightforward interpretation of the results. | PMC10523642 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07648-8. | PMC10523642 | ||
Keywords | PMC10523642 | |||
Introduction | NB | REGRESSION | Zero-inflated (ZI) non-negative count data frequently arise in medical studies, e.g., number of clinic visits, admissions, days in hospital, number of serious illnesses, and medical costs. This data has the following distinct characteristics: (1) the presence of a large proportion of zero values (i.e., zero inflation [While ZI models have been previously compared to their non-inflated counterparts, the conclusions of which model outperforms the other have been inconsistent. For example, Du et al. [The current study is motivated by a recent clinical trial where, under a Bayesian framework, the ZINB model did not sufficiently outperform the NB model when modeling ZI count outcomes obtained in a trial of children with medical complexity [In this simulation study, we re-analyzed the trial data under a Frequentist framework and further investigated which data properties have the largest effect on model fitness under varying sample sizes and degrees of zero inflation. We first compare the model performance of NB and ZINB models based on AIC and then examine whether any characteristics of a ZI outcome influence the model performance and effect sizes. Our hypotheses are as follows. First, we hypothesized that there would be no significant differences between the NB and ZINB regression models in terms of marginal treatment effects, bias, and coverage. Second, we hypothesized that other data characteristics such as skewness and variance of the non-zero part of the data, rather than the number of zero counts in the ZI data and the degree of overdispersion, would be more important in deciding between NB and ZINB models. Last, we hypothesized that the choice of the | PMC10523642 |
Methods | NB | REGRESSION | The overall scheme of this simulation study is depicted in Fig. Overall flow chart of the study. We first fitted DD NB and ZINB regression models to the Telemedicine Study dataset. Based on the coefficients from data-derived (DD) models, we generated 5000 synthetic datasets. Unique characteristics of synthetic outcomes were recorded. Synthetic data were fitted with NB and ZINB regression models referred to as sim. models. Each sim. model produced AIC and coefficients of a treatment group variable. Bias and coverage of the treatment coefficient were also calculated. We then created a new dichotomous outcome variable indicating whether the ZINB model gave a better fit to the data based on the AICs from the sim. NB and ZINB models. Using characteristics of the synthetic outcomes as predictors, we performed a ridge logistic regression to identify the important characteristics in determining model preferenceDescription of notations used in the study (data-derived (DD)) | PMC10523642 |
Motivating example | NB, illness | REGRESSION, SECONDARY | Telemedicine (TM) is an emerging platform for the delivery of health-related services and medical information via telecommunication technology such as computers and smartphones. The COVID-19 pandemic heightened the importance and value of these contactless healthcare services. Previuosly [In this current study, the primary outcome of interest is the number of serious illness episodes. A serious illness episode was defined as a case in which a patient either had a hospital stay > 7 days was admitted to the pediatric intensive care unit (PICU) or died during the same hospitalization. Approximately 72.7% of the primary outcome values were zero (70% and 75.6% in the CC alone and CC + TM groups, respectively). Here, we also include two secondary outcomes: (1) days in the hospital and (2) care days outside the home. The distribution of days in hospital is similar to the primary outcome, with the exception of a few extreme observations (median 0, interquartile range 0–6, maximum 92). The distribution of care days outside the home differs because the percentage of zero counts is only 5.2%. The characteristics of the three observed outcomes are shown in Table Characteristics of the observed outcomes (Var., variance, % of 0’s, percentage of zero counts) and a list of covariates for adjustmentSimilar to the original analyses of these outcomes, we include three variables as predictors: (1) treatment group (CC alone = 0; CC + TM = 1); (2) age strata (< 2 years; ≥ 2), (3) baseline risk (risk level 1 [mechanical ventilation], risk level 2 [equal to or above the expected median risk but not ventilator-dependent], and risk level 3 [below the expected median risk]). Length of follow-up (in days) is included as an offset. Using the three outcomes and observed predictors, we performed a NB and ZINB regression analysis. The regression coefficients from the NB and ZINB models were then used as | PMC10523642 |
Summary of NB and ZINB distributions | REGRESSION | The ZINB distribution is a mixture distribution in which a mass of The expected count is In the ZINB regression model, the parameters Here, | PMC10523642 | |
Simulation of synthetic data | REGRESSION | To obtain the simulated outcomes, two components are required: (1) regression coefficients from the DD models and (2) synthetic predictors (i.e., a treatment group variable and covariates for adjustment). The amount of zero counts in the simulated outcomes reflects both the regression coefficients and the synthetic predictors. Synthetic predictors were generated using three sampling distributions: (1) binomial distribution for the treatment group, (2) multinomial distribution for baseline risk, and (3) truncated normal distribution for age. The values of the parameter(s) in the sampling distributions were generated using a uniform distribution with parameters reflecting the observed data (see Additional file | PMC10523642 | |
Sensitivity analysis: sample size | Additionally, we varied the sample size of the synthetic data (60, 80, 100, 200, 600, and 800) to assess whether the results behave differently depending on the sample size. We used the same model parameters and distributions to simulate the | PMC10523642 | ||
Analysis of synthetic data | NB | Each of the three outcomes in the synthetic datasets was analyzed with two different GLMs: NB and ZINB models. For each model, we calculated bias, mean squared error (MSE), and coverage for | PMC10523642 | |
Ridge logistic regression using unique data characteristics as predictors | NB | We constructed a new dichotomous outcome variable (either 0 or 1) indicating whether the ZINB model gave a better fit to the synthetic dataset based on the AIC from the Adjusted odds ratio for a preference for a ZINB model (over an NB model in terms of AIC) regardless of the type of the DD modelUnique characteristics of the synthetic primary outcomes (Var., variance, % of 0’s, percentage of zero counts). Top: simulated from the data-derived (DD) NB model. Bottom: simulated from the DD ZINB modelNote that the Vuong test [ | PMC10523642 | |
Results | PMC10523642 | |||
Simulation metrics | As shown in Table Bias, mean squared error (MSE), and coverage for treatment group coefficient, | PMC10523642 | ||
Important predictors of ZINB being preferred | NB | REGRESSION, SENSITIVITY | Regardless of the The results from the ridge logistic regression analysis indicated that the mean of the non-zero part of the outcome was the strongest positive predictor of a preference for a ZINB model, with OR of 1.71 (Fig. Sensitivity analysis: adjusted odds ratio for a preference for a ZINB model (over an NB model in terms of AIC). Left: based on the results from DD NB models. Right: based on the results from DD ZINB models | PMC10523642 |
Discussion | NB | REGRESSION | The aim of this study was to compare the performance of NB and ZINB regression models in terms of bias, MSE, and coverage and to determine which properties of zero-inflated count data are better described by a ZINB model. Our simulation results indicated that a ZINB regression model does not necessarily outperform an NB model when evaluating ZI medical count outcomes obtained in a trial of children with medical complexity. This is consistent with our original analysis conducted under a Bayesian framework. Even when data were simulated from an underlying ZINB distribution, the NB model had a very similar or even smaller relative bias and MSE for the marginal treatment effect. This suggests that when data is explained and predicted using regression coefficients, as is common in medical and epidemiological studies, there is no significant difference between the NB and ZINB models. Additionally, we want to emphasize that determining the best-fitting model using quantitative model selection criteria (e.g., AIC) is not the only goal of statistical modeling. The ultimate goal of statistical modeling, as Hand [When comparing which model gave a better fit to simulated data, our results showed that the NB model outperformed that of a ZINB model in terms of bias, MSE, and coverage for the treatment group coefficients, even with outcomes generated from a ZI distribution. It signifies that, in terms of the results (e.g., an intervention effect) in which medical professionals are primarily interested, there is no substantial difference between the ZI and non-ZI regression models, even when the outcome contains excess zeros. Note that, when we used a primary outcome with a sample size of 800, the coverage from the From the multivariable ridge logistic regression, we observed that the proportion of zeroes played a smaller role in predicting a preference for the ZINB model than the MLE of the shape parameter, when the DD ZINB model was used to generate synthetic primary outcomes. This result indicates that, contrary to popular belief, the percentage of zero counts in predicting a preference for (or fitness of) the ZINB model (over the NB model) is not as substantial as we would assume.For However, there are the following three caveats to consider. First, we exclusively considered the use of the ZINB model (and the ZIP model without any subsequent results described) in this study, which assumes that zero counts are from either the In spite of the caveats discussed, this study is significant because it sheds fresh light on modeling with zero-inflated outcomes, which are frequently observed in medical data. We recommend that the percentage of zero counts in the outcome not be used as the sole and primary reason for selecting ZI regression models. Investigators should also consider other data characteristics such as the mean and skewness of the non-zero part of the outcome when choosing a model for medical count data. In addition, if the performance of the NB and ZINB regression models is reasonably comparable even with ZI outcomes, we advocate the use of the NB regression model due to its clear and straightforward interpretation of the results. | PMC10523642 |
Acknowledgements | Not applicable | PMC10523642 | ||
Authors’ contributions | KL and CP designed the study. KL analyzed the data and performed the simulation studies. KL and CP drafted and revised the manuscript. RM, EA, and JT provided trial data in the required format. All authors agreed to be responsible for all aspects of the manuscript. All authors read and approved the final manuscript. | PMC10523642 |
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