BACKGROUND:The management of multimorbidity often requires applying multiple disease-specific guidelines, which may lead to harmful disease and drug interactions. The objective of the study was to collect the opinions of leading experts on factors influencing the use of guidelines in decision-making in multimorbidity management from a multidisciplinary perspective, and provide empirical insights to inform guideline-based decision support. METHODS:We conducted a series of semi-structured interviews with experts in multimorbidity research and practice and guideline development to participate. Interviewees were selected using purposive sampling. Our interviews covered the current use of clinical guidelines in multimorbidity management, key barriers and facilitators, and priority action areas. Thematic analysis was performed using NVivo 12.0. RESULTS:Fifteen experts from nine countries were interviewed. The lack of multimorbidity-specific guidelines and recommendations may lead healthcare providers to either rely solely on personal experience, or follow guidelines without considering the needs and comorbidities of individual patients. Major barriers to guideline application include insufficient evidence and limited awareness and training among clinicians in both multimorbidity management and guideline implementation. The interviewees emphasized flexible use of guidelines, prioritizing patient values and preferences, and individualized management goals informed by (rather than strictly adhering to) guidelines. CONCLUSIONS:Applying guidelines in multimorbidity care faces major evidence and applicability gaps. Particularly the generation of high-quality clinical evidence specific to multimorbidity, enhancing the methodological rigor in guideline development, and improvement of the contextual relevance and usability of guidelines in real-world settings need more attention.
OBJECTIVE:To develop and validate a rapid, evidence-based benefit-risk assessment index for off-label drug use in pediatrics, thereby promoting standardized clinical decision-making. METHODS:Under the auspices of the Guangdong Pharmaceutical Association, a multidisciplinary expert panel from pediatrics, pharmacy, methodology, and ethics was convened. Systematic literature searches informed a preliminary index framework. Three Delphi rounds refined indicators. Weights were assigned using the analytic hierarchy process. Expert-based validation involved 20 hematology-oncology experts assessing 10 cases; intraclass correlation coefficient (ICC) and Spearman's correlations evaluated reliability and validity. RESULTS:The index consists of 2 primary dimensions (benefits: 56 points; risks: 44 points), 10 third-level, and 40 fourth-level indicators, with five prerequisites (e.g., no alternatives, informed consent). The ICC was 0.77 (good reliability); Spearman's correlations were rs = 0.97 (benefits) and rs = 0.68 (risks) (both p < 0.05), indicating strong alignment with expert consensus. Junior experts showed lower correlations (benefits rs = 0.89; risks rs = 0.56) than seniors (benefits rs = 0.97; risks rs = 0.78), highlighting the system's role in standardizing assessments. CONCLUSION:This quantitative index provides an evidence-based tool for pediatric off-label drug decisions, supporting clinicians, policymakers, and standardization efforts.
AIM:To investigate associations of symptomatic, radiographic, and structural knee indicators with radiographic osteoarthritis (OA) progression in the contralateral knee among individuals with or at risk of OA. METHODS:Data were obtained from the Osteoarthritis Initiative Database (accessed on December 21, 2022), with knees as the unit of analysis. Baseline exposures included symptomatic measures (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], Knee injury and Osteoarthritis Outcome Score), radiographic features (radiographic OA status, Kellgren-Lawrence [KL] grades, joint space width [JSW], and alignment), and magnetic resonance imaging (MRI)-based structural abnormalities (MRI Osteoarthritis Knee Score [MOAKS]-assessed lesions including cartilage defects, bone marrow lesions, meniscal morphology, Hoffa-synovitis, and effusion-synovitis). Outcomes were 4-year contralateral KL grades and 4-year JSW change. Generalized estimating equation models were used. RESULTS:Each 1-point increase in WOMAC total score was associated with increased contralateral KL grades (β = 0.002, 95% confidence interval [CI], 0.001 to 0.003) and greater medial JSW narrowing (β = -0.005 mm, 95% CI, -0.007 to -0.003 mm). Radiographic OA status was associated with higher KL grades (β = 0.112, 95% CI, 0.088 to 0.136) and reduced medial JSW (β = -0.179 mm, 95% CI, -0.236 to -0.122 mm) and lateral JSW (β = -0.168 mm, 95% CI, -0.257 to -0.079 mm). MRI-based analyses showed that MOAKS-defined structural damage was associated with greater contralateral JSW loss, with compartment-specific patterns. Each 1-point increase in medial tibiofemoral (TF) joint bone marrow lesion (BML) size was associated with a 0.045 mm decrease in contralateral medial JSW (95% CI, -0.065 to -0.025 mm), while each 1-point increase lateral TF joint BML size was associated with a 0.048 mm decrease in contralateral lateral JSW (95% CI, -0.084 to -0.012 mm). CONCLUSIONS:Worse symptomatic, radiographic, and structural knee status is associated with contralateral radiographic OA progression, suggesting contralateral knee condition should be considered in OA evaluation.
OBJECTIVE:To evaluate harms reporting practices in placebo-controlled randomized clinical trials (RCTs) of Chinese herbal medicine (CHM) formulas published in Quartile 1 (Q1) English-language and Tier-1 Chinese journals. METHODS:This systematic survey evaluated harms reporting in CHM formula RCTs. We systematically identified eligible RCTs published in English-language journals Q1 (2024 Journal Citation Reports) and Chinese Tier-1 journals (2023 Traditional Chinese Medicine ranking). Two reviewers independently evaluated harms reporting using items derived from the CONSORT Extension for Harms (CONSORT Harms) recommendations and CHM formula-specific reporting elements. RESULTS:Among 96 eligible RCTs (49 English Q1; 47 Chinese Tier-1), only 19.8% (n = 19) of trials had a published protocol, with a significantly higher proportion in English Q1 journals (p < 0.001). Only one trial explicitly reported adherence to the CONSORT Harms extension (2004 or 2022). Syndrome differentiation was significantly more frequent in Chinese Tier-1 journals than in English Q1 journals (76.6% vs. 38.8%, p < 0.001). Sixty-seven percent of studies (n = 64) did not report methods for assessing the relationship between harms and interventions, and 15.6% (n = 15) relied solely on clinical judgment. Eighty percent of studies (n = 77) did not report statistical methods for harms analysis. In the results section, 62% (n = 59) did not present harms data in tables. CONCLUSIONS:Harms reporting in CHM formula RCTs remains inadequate. Routine adoption of the CONSORT Harms framework, together with CHM formula-specific harms reporting elements, is needed to improve transparency and facilitate the interpretation of harms data in CHM formula research.
With the accelerating population aging, the number of older adult patients with lung cancer continues to increase. These patients often present with multiple chronic diseases and geriatric syndromes, resulting in more complex perioperative management and significantly increased surgical risks. This guideline was developed and reported on the basis of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist. Focusing on 28 key clinical issues commonly encountered among older adults with lung cancer, such as frailty, malnutrition, and falls, a total of 55 recommendations were formulated. This guideline aims to provide standardized perioperative management strategies through comprehensive geriatric assessment, comorbidity management, and early identification and intervention for complications to reduce the incidence of postoperative complications and improve patients' quality of life.
OBJECTIVE:Cardiovascular-kidney-metabolic (CKM) syndrome links metabolic, kidney, and cardiovascular disorders, but its burden among women of reproductive age (WRA) remains poorly understood. We quantified the global burden and trends of key CKM-related conditions and high body mass index (BMI)-attributable burden among WRA. METHODS:Using global burden of disease data from 1990 to 2021, we quantified six CKM-related disease outcomes and the burden attributable to high BMI. Trends were assessed using estimated annual percentage changes (EAPCs), and burden was projected to 2050 using Bayesian age-period-cohort models. RESULTS:In 2021, diabetes mellitus had the highest incidence rate (273.37 per 100,000 population; 95% uncertainty interval [UI], 204.50-353.52), ischemic heart disease the highest death rate (8.48 per 100,000 population; 95% UI: 7.68-9.35), high BMI the highest attributable disability-adjusted life-year (DALY) rate (641.53 per 100,000 population; 95% UI: 283.14-998.09), and chronic kidney disease the highest prevalence rate (6805.22; 95% UI: 5319.94-8575.90). From 1990 to 2021, the age-standardized death rate attributable to high BMI increased (EAPC, 0.43%; 95% confidence interval [CI]: 0.37%-0.50%), whereas the age-standardized DALY rate (ASDALYR) for stroke declined (-1.93%; 95% CI: -2.01% to -1.86%). Low-middle sociodemographic index regions had the highest ASDALYR in 2021 (2757.18; 95% UI: 2056.45-3505.64). Under historical-trend assumptions, high-BMI-attributable DALYs were projected to remain dominant through 2050 (1051.49; 95% UI: 235.36-1868.06), with the fastest projected increase in lower extremity peripheral arterial disease (3.39%; 95% CI: 3.13%-3.66%). CONCLUSIONS:Among WRA, CKM-related burden was substantial and varied across sociodemographic index quintiles. These findings support intensified adiposity control and context-specific prevention to reduce future burden through 2050.
OBJECTIVE:To systematically analyze the comorbidity status, polypharmacy patterns, and potential medication risks among hypertensive patients attending cardiology departments in tertiary hospitals in China based on real-world outpatient prescription data, providing real-world evidence to describe the medication complexity in this population. METHODS:A cross-sectional study design was employed. Prescription data of hypertensive patients from the cardiology outpatient departments of 56 tertiary hospitals in mainland China in 2017 were extracted. Diagnosis data, medication data, potentially inappropriate medication (PIM) and potential drug-drug interactions (pDDI) were analyzed. Continuous variables were compared using t‑tests or Mann-Whitney U tests and reported as mean ± standard deviation or median (interquarile range). Linear regression assessed age‑related trends in medication counts. All tests were two‑sided with α = 0.05. RESULTS:83.3% of patients had at least one other comorbid condition. The average number of medications per patient was 7.44 ± 5.98, showing a positive correlation with age. Among elderly patients, 10%-15% were exposed to PIMs, and we identified 12 clinically significant pDDI pairs in the cardiology outpatient prescription scenario. CONCLUSIONS:Multimorbidity and polypharmacy are prevalent among hypertensive patients attending cardiology departments in tertiary hospitals in China. These findings serve as a historical baseline rather than direct clinical guidance. Based on the high prevalence of PIMs in elderly patients and typical clinically significant pDDI identified in this cohort, targeted medication safety strategies (including tailored Medication Therapy Management for multimorbid hypertensive patients and appropriate deprescribing of high-risk agents in the elderly) are suggested to optimize patient-centered comorbidity management.
OBJECTIVE:Very low birthweight infants (VLBWIs) are at high risk of pulmonary hemorrhage, yet practical and effective early prediction tools remain limited. The study aimed to develop an early predictive model for pulmonary hemorrhage in VLBWIs to support risk management. METHODS:VLBWIs admitted to Children's Hospital of Nanjing Medical University were included in the development cohort (January 1, 2019, to January 1, 2023), while those admitted between January 2, 2023, and July 31, 2025, formed the temporal validation cohort. Infants from Jiangsu Maternal and Children Hospital were used as an external validation cohort. Prediction was performed at 24 h of life, using variables collected within the first 24 h after birth. Eight machine learning algorithms were compared for model development and evaluation. RESULTS:The development, temporal validation, and external validation cohorts included 775, 208, and 314 VLBWIs, respectively. Seven variables were selected for the final logistic regression model, which was implemented as a web-based nomogram. The model showed good discrimination, with area under the receiver operating characteristic curves (AUROCs) of 0.841 (95% confidence interval [CI]: 0.800-0.883) in the training set, 0.836 (95% CI: 0.766-0.906) in the internal validation set, and 0.834 (95% CI: 0.768-0.900) in the temporal validation set. Calibration was acceptable in the training and internal validation sets, with some decline in the temporal validation cohort (Brier score 0.181), but improved after exploratory recalibration. External validation yielded an AUROC of 0.778 (95% CI: 0.709-0.847) with acceptable calibration. CONCLUSIONS:This model predicts subsequent pulmonary hemorrhage in VLBWIs within 24 h after birth. Decision curve analysis indicated favorable clinical utility.
Meta-analyses of correlation coefficients are widely used to synthesize evidence on associations among variables in psychology, medicine, education, and the social sciences, yet practical guidance on how to implement these analyses in standard software remains limited. In this article, we provide a step-by-step introduction to conducting meta-analyses of correlation coefficients in Stata and R, with focus on the use of Fisher's z transformation for valid estimation, weighting, and interpretation. We first provide a brief review of Fisher's z transformation as a statistical foundation for synthesizing correlation coefficients. Using a simple toy dataset consisting of seven artificial studies, we then illustrate how to properly implement correlation meta-analyses in Stata, highlighting the behavior of forest and funnel plots when Fisher's z transformation is applied and when it is omitted. Parallel workflows are demonstrated in R using the "meta" and "metafor" packages, including effect size specification, fitting under the random-effects model, and generation of forest and funnel plots. We compare the results and visualizations produced by the different software tools and outline their respective functionalities. Sample code and practical recommendations are provided to help researchers avoid common pitfalls and to conduct correlation-based meta-analyses that are statistically sound and readily interpretable.
ABSTRACT Aim Integrating randomized controlled trials (RCTs) and real‐world studies (RWS) requires balancing internal and external validity to achieve target validity. We extended external validity assessment to better capture contextual complexity and diversity, integrating it with established internal validity tools to refine the target validity scoring system. Then, we proposed an Internal Validity‐Gated Dual Weighting (IVDW) strategy, which applies external validity weights to studies exceeding a predefined internal validity threshold. Methods The scoring system was refined through a two‐round Delphi process and Analytic Hierarchy Process to ensure content validity and derive item weights. IVDW was implemented in both frequentist and Bayesian frameworks and compared with four alternatives: Equal‐Weighting, Dual‐dimensional Weighting (DDW), Conditional Exclusion‐based Dual‐weighting (CEDW), and Internal‐validity‐Only Weighting (IVOW), in a novel synthesis of neoadjuvant chemoimmunotherapy in older adults with non‐small cell lung cancer. Results Studies with concurrently high internal and external validity had risk difference estimates below 0.2. IVDW more effectively downweighted low‐internal‐validity studies than DDW and reduced reliance on low‐external‐validity studies compared to IVOW. It improved interpretability by explicitly balancing validity dimensions while maintaining higher evidence inclusion than CEDW. When combined with the quality effects model, IVDW produced estimates aligned with high target validity studies. Conclusions The proposed target validity scoring system, combined with the IVDW strategy, steers effect estimates toward studies with higher internal and external validity. It extends a novel perspective for evidence synthesis and enhances the external validity of meta‐analytic findings in real‐world clinical decision‐making.
BACKGROUND:Lumbar disc herniation (LDH) is a common cause of low back pain and disability. Herbal medicine (HM) is increasingly used for LDH in Korean medicine (KM) practice, but evidence synthesis is limited by inconsistent outcome selection and reporting. We aimed to develop a core outcome set (COS) to standardize reporting in HM studies of LDH in KM practice. METHODS:The study followed the Core Outcome Set-STAndards for Development (COS-STAD), with reporting guided by the Core Outcome Set-STAndards for Reporting (COS-STAR). Candidate outcomes were identified through a systematic review of Korean (OASIS, ScienceON) and international (PubMed, CENTRAL) databases from inception to December 2024, supplemented by clinical practice guidelines and textbooks. Outcomes were refined into predefined domains and potential effect modifiers (EMs) were identified. A two-round Delphi survey with experts was conducted, followed by a Delphi survey with KM clinicians to assess feasibility in practice. A structured consensus meeting was held to finalize the COS. RESULTS:Of 1426 records, 122 studies were included. Ninety-six outcomes were refined to 75 distinct outcomes across six domains, alongside 15 EMs. Delphi participation included 25 experts in Round 1, 23 experts in Round 2, and 10 KM clinicians in the clinician Delphi survey. The final Core Outcome Set for Herbal Medicine Treatment of Lumbar Disc Herniation (COS-HM-LDH) comprised 13 outcomes and 10 EMs. CONCLUSION:COS-HM-LDH provides a standardized minimum set of clinically important LDH outcomes and EMs for HM trials and real-world studies in KM practice, improving consistency and comparability across studies.
AIM:The aim of this study is to evaluate the efficacy and safety of blood-activating and stasis-removing Chinese patent medicines (BASR-CPMs) during the perioperative period of percutaneous coronary intervention (PCI) for myocardial infarction (MI). METHODS:We searched eight databases (PubMed, Embase, the Cochrane Library, Web of Science, CNKI, WanFang Data, SinoMed, and VIP) from database inception to February 15, 2025, for randomized controlled trials (RCTs) comparing standard care plus BASR-CPMs versus standard care alone (or with other BASR-CPMs) in MI patients undergoing PCI. A Bayesian network meta-analysis was conducted to estimate relative effects. Primary outcomes included major adverse cardiovascular events (MACE) and major adverse cardiac and cerebrovascular events (MACCE), while key secondary outcomes included thrombolysis in MI (TIMI) grade 3 flow, angina, and bleeding events. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. The certainty of evidence was evaluated using the GRADE framework. A protocol of the systematic review and network meta-analysis was registered with PROSPERO (CRD420251048208). RESULTS:We included 160 RCTs (21,147 participants) evaluating 25 BASR-CPMs. Regarding hard clinical endpoints, no BASR-CPMs differed significantly from standard care for MACE or MACCE at any time point. For example, Tongxinluo capsule showed no significant reduction in MACE at 1 month (relative risk [RR] 0.62, 95% credible interval [CrI] 0.11 to 1.70; low certainty). Tongxinluo capsule may improve TIMI grade 3 flow immediately after PCI (RR = 1.12, 95% CrI: 1.04-1.26; low certainty) and at 3 months (RR = 1.47, 95% CrI: 1.10-1.98; moderate certainty). Danhong injection (RR = 1.15, 95% CrI: 1.02-1.31) and Shexiang Baoxin pill (RR = 1.15, 95% CrI: 1.02-1.30) may also improve TIMI grade 3 flow immediately after PCI (moderate certainty). For reducing angina incidence at 1 and 6 months, Tongxinluo, Danhong, Salvianolate injection, Shexiang Baoxin, Guanxin Shutong, and Shexiang Tongxin dripping pill showed potential benefits (low to high certainty). Most interventions did not increase bleeding risk, and Tongxinluo possibly reduced adverse effects (low certainty). CONCLUSIONS:Exploratory findings suggest that BASR-CPMs, notably Tongxinluo, Danhong, and Shexiang Baoxin, improve immediate reperfusion and reduce angina recurrence post-PCI in MI patients. These intermediate benefits do not translate into reductions in hard clinical outcomes. Further rigorous RCTs are needed to confirm their long-term impact on MACE and MACCE.
OBJECTIVES:To evaluate the status and methodological quality of randomized controlled trials published in 2024 on Chinese patent medicines and Classic Traditional Chinese Medicine Prescriptions, providing evidence for clinical practice and policy. METHODS:We systematically searched multiple Chinese and English databases and trial registries for randomized controlled trials (RCTs) on Chinese patent medicines (CPMs) and Classic Traditional Chinese Medicine Prescriptions (CTCMPs) published in 2024. Two researchers independently screened studies, extracted data, and assessed methodological quality using the Cochrane RoB tool. Inter-rater reliability was evaluated using Kappa statistics and intraclass correlation coefficient. Spearman's correlation and Wilcoxon rank-sum tests were performed to analyze factors influencing methodological quality. RESULTS:In 2024, 1874 RCTs were included (1550 CPM, 324 CTCMP). Circulatory and digestive diseases predominated in CPM and CTCMP studies, respectively. Two-arm "Chinese medicine plus Western medicine" designs were mainstream. CPM RCTs favored physical/chemical outcomes, while CTCMP RCTs prioritized symptoms/signs outcomes; 169 patient-reported outcomes were identified. Most studies had small samples (100 cases) and were single-center. Methodological quality revealed adequate randomization but serious deficiencies in allocation concealment and blinding. Ethics approval (CPM≈68.5%, CTCMP≈61.1%) and trial registration (CPM≈3.8%, CTCMP≈0.9%) were suboptimal. Funding, higher journal IF, and multicenter design were positively associated with ROB scores. CONCLUSIONS:This evidence mapping reveals a significant disconnect between the quantity and quality of randomized controlled trials in Traditional Chinese Medicine. Persistent methodological weaknesses undermine evidence reliability. Future research should prioritize methodological rigor, adequate statistical power, and prospective trial registration. There is an urgent need to develop a dedicated evaluation framework that captures both methodological quality and clinical value.
Background: The routine approach in evidence synthesis of adverse events is to estimate the odds ratio or risk ratio of each individual study and then synthesize the study-specific effects for a pooled average estimate, while seldom consider the potential imbalanced duration of exposures of study arms. This article aims to investigate the potential impact of imbalanced exposure time on harm effects. Methods: We simulated individual participant time-to-event data based on Cox proportional hazard model, with Weibull function to reshape the distribution of the hazards. We further collapsed the data into aggregated one and fitting both hierarchical Binomial regression model and hierarchical Poisson regression model to estimate the pooled RR and incidence rate ratio (IRR). The percentage bias, mean squared error, and coverage probability were examined. Results: Our results suggested that imbalanced exposure time between study arms can have substantial impact on the estimation of harm effects in evidence synthesis, especially when the extent of the imbalance exceeds 20%. Estimating an IRR to address the imbalanced exposure time only made sense for non-recurrent events when the between-study heterogeneity is small or moderate. A case study by 22 ongoing trials verified the potential biased estimation when exposure time was imbalanced between study arms. Conclusions: It is inappropriate to ignoring exposure time when there is a large difference (> 20%) between study arms; while the IRR could be used in some cases, collecting individual participant data for evidence synthesis of adverse events for time-to-event data should be the primary consideration.
Objective Evidence-based medicine emphasizes clinical research driven by important questions, yet Chinese medicine lacks practical quantitative tools to identify such questions. We developed the Chinese Medicine Interventional Clinical Trials Research Question Importance Tool (CMICT-RQIT) to support topic selection and provide transparent criteria for proposal review, promoting high-quality clinical research in Chinese medicine.Methods This study followed internationally accepted procedures of conceptualization and operationalization. Using a mixed-methods approach-including a literature review, qualitative interviews, Delphi surveys, expert consensus meetings, and the analytic hierarchy process-we developed the CMICT-RQIT. CMICT-RQIT was prespecified and interpreted as a formative/composite multicriteria decision-support tool.Results Following a standardized development process comprising three stages-framework construction, tool development, and tool evaluation-the CMICT-RQIT V1.0 was established. It consists of four domains, 10 facets, and 24 items, each with corresponding composite weights, item explanations, scoring criteria, and an operations manual. Exploratory traditional psychometric analyses showed limited internal consistency and poor structural fit, consistent with the formative/composite nature of the tool and should not be interpreted as evidence that all items measure a single latent trait.Conclusions CMICT-RQIT V1.0 can assist researchers in selecting research topics, with its greatest value lying in providing a concise summary of the importance of research question along with a comprehensive 24-item checklist for clinical investigators. At the same time, it offers reviewers transparent criteria for assessing the importance of research questions, thereby promoting the objectivity and fairness of evaluations. CMICT-RQIT V1.0 should be used primarily as a structured checklist and decision-support index.
OBJECTIVE:To assess associations of the triglyceride-glucose (TyG) index and cholesterol high-density lipoprotein glucose (CHG) index with overall survival (OS) and progression-free survival (PFS) in gastric cancer (GC), and to explore whether prognostic value differs by pathological stage. METHODS:We conducted a retrospective cohort study using routinely collected electronic medical record data from West China Hospital, Sichuan University, including patients who underwent GC resection between 2008 and 2021. TyG and CHG were calculated from preoperative laboratory parameters. Associations with OS and PFS were assessed using multivariable Cox models, with subgroup analyses by pathological stage. Kaplan-Meier and time-dependent receiver operating characteristic analyses were also performed. RESULTS:In the overall cohort, TyG and CHG have no independent association with OS or PFS after adjustment. Subgroup analyses stratified by cancer stage showed higher CHG index was associated with worse OS in Stage 1 (hazard ratios [HR] = 2.038, 95% confidence interval [CI]: 1.336-3.110, p < 0.001), whereas higher TyG index was associated with better OS in Stage 4 (HR = 0.860, 95% CI: 0.756-0.980, p = 0.023). Kaplan-Meier analyses supported these stage-specific associations. CHG showed the best predictive performance for Stage 1 OS, while TyG index showed relatively stable discrimination for Stage 4 OS. CONCLUSIONS:The prognostic value of TyG and CHG in GC appears to be stage-dependent. CHG index may be more useful in stage 1, whereas lower TyG index may indicate poorer prognosis in stage 4.
