ABSTRACT Background Obesity is a key contributor to type 2 diabetes, and weight loss is a central component of diabetes management. Although clinical guidelines recommend that healthcare providers offer weight management advice, its real‐world impact remains unclear. Objective This study assessed the associations of doctor‐advised and self‐initiated weight management with weight loss among individuals with type 2 diabetes who are overweight or obese. Methods Data were obtained from the National Health and Nutrition Examination Survey (NHANES 2011–2018). People with diabetes and overweight or obesity (body mass index ≥ 25 kg/m2) were categorized into four groups according to doctor‐advised weight loss and weight management status. Outcomes included one‐year weight change, assessed both continuously (percentage change) and categorically (≥ 5% and ≥ 10% weight loss). Linear regression was used for continuous outcomes and Poisson regression with robust standard errors for categorical weight loss. Results Among 1715 individuals (61.1 ± 12.4 years, 49.1% female), 1020 received doctor‐advised weight loss, and 89.6% initiated weight management. However, individuals who received advice achieved less weight loss than those not advised, particularly among those who did not engage in weight management (β: 5.07, 95% CI 3.07 to 7.07, p < 0.001). Individuals who received advice were also substantially less likely to achieve ≥ 5% (RR 0.15, 95% CI 0.06 to 0.39, p < 0.001) or ≥ 10% weight loss (RR 0.20, 95% CI 0.10 to 0.41, p < 0.001). Conclusions Only three out of five participants with diabetes and overweight or obesity were advised by healthcare providers to lose weight. While weight loss advice spurred individuals to engage in weight management, those who received weight loss advice encounter greater challenges in reaching weight loss targets.

OBJECTIVE:To investigate the associations of maternal and personal smoking with the risk of knee, hip, hand, and overall osteoarthritis (OA) and the role of genetic predisposition to OA. METHODS:A total of 321,075 UK Biobank participants (mean age 56 years, 55% female) without OA at baseline were included; 29.9% reported maternal smoking, 24.3% reported former smoking, and 9.5% reported current smoking. Maternal smoking around childbirth (yes/no) and personal smoking status (never/former/current) and dose (pack-years) were self-reported by the participants. Cox proportional hazards models were used to explore the associations of maternal and personal smoking status and personal smoking dose with the risk of OA. Genetic susceptibility of OA was assessed using polygenic risk scores (PRS). RESULTS:During follow-up, 18,470 (5.8%), 12,064 (3.8%), 6605 (2.1%) and 52,853 (16.5%) participants developed knee, hip, hand, and overall OA, respectively. Both maternal and personal smoking were positively associated with the risk of knee, hip, hand, and overall OA (maternal smoking hazard ratio [HR]=1.08 to 1.23; personal smoking HR=1.18-1.40) . There were significant dose-responsive associations between personal smoking dose and OA risk (p for trend<0.05). The association between maternal and personal smoking and OA risk was similar across different PRS strata. CONCLUSION:Both maternal and personal smoking are independently associated with an elevated risk of OA. These associations are universal across different genetic susceptibility of OA.

The prognostic impact of exposure to PM2.5 and its components across multiple time windows in DLBCL remains unclear. A total of 1,154 newly diagnosed DLBCL patients were included across seven medical centers. Individual exposures to PM2.5 and its five chemical components, including SO42-, NO3-, NH4+, OM, and BC, were estimated across four exposure windows of 1, 3, 5, and 10 years before diagnosis. OM averaged over 1 year (HR = 1.319; 95% CI: 1.035-1.681) and 5 years (HR = 1.325; 95% CI: 1.070-1.641), as well as SO42- averaged over 3 years (HR = 1.348; 95% CI: 1.008-1.801), were associated with worse prognosis in DLBCL patients. Dose-response patterns were observed in quartile-based analyses. In multi-pollutant analysis, the combined mixture of five components averaged over 3 years was also associated with adverse prognosis. However, given the observational design, causal inference cannot be established, and further validation is warranted.

OBJECTIVES:To identify and validate novel urinary protein biomarkers associated with disease activity in RA, and to investigate their potential biological roles. METHODS:We employed a multi-phase strategy integrating proteomic discovery, biomarker validation, population-based analysis and mechanistic studies. Differentially expressed proteins (DEPs) were first identified using data-independent acquisition-based proteomic profiling in a discovery set comprising RA patients and healthy controls (HCs). Candidate proteins were subsequently validated by ELISA in two independent validation cohorts. Population-based associations were assessed in two RA cohorts (n = 301 cross-sectional; n = 214 longitudinal), with disease activity evaluated using VAS and DAS28 scores. Functional relevance was further examined in synovial tissues, fibroblast-like synoviocytes (FLS) and cytokine assays. RESULTS:A total of 209 DEPs were identified between RA patients and HCs, with enrichment analyses highlighting immune-related pathways. Among these, IGLV3-1 demonstrated high diagnostic potential (AUC = 0.99) and was consistently validated in two independent cohorts. In population-based analyses, IGLV3-1 levels were positively associated with both VAS (β = 1.070, 95% CI: 0.264-1.875) and DAS28 scores (β = 0.672, 95% CI: 0.029-1.315) and predicted a reduced likelihood of VAS pain improvement (OR = 0.188, 95% CI: 0.047-0.746). Mechanistically, IGLV3-1 was upregulated in RA synovial tissues and FLS, and positively correlated with IL-6, IL-8 and IL-12p70 levels. Its knockdown via siRNA in FLS led to reduced expression of these pro-inflammatory cytokines at both mRNA and protein levels. CONCLUSION:IGLV3-1 is a novel urinary protein biomarker that reflects RA disease activity and predicts clinical outcomes.

Previous studies have been inconsistent concerning the associations of smoking and alcohol consumption with the prognosis of diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the associations of smoking and drinking status with overall survival (OS) in male patients with DLBCL. A total of 371 male patients with newly diagnosed DLBCL were retrospectively enrolled from eight medical centers. Smoking and drinking status were assessed as binary variables (yes or no). Inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for potential confounders. Kaplan–Meier survival analysis and Cox proportional hazards models were used to assess associations. Overall, 17.3

Xicheng Chen,1,* Linyu Huang,2,* Qiming Zhang,1,* Xing Xing,3 Shuo Zhang,4 Chunling Wang,5 Ling Wang,6 Ziyuan Shen,7,* Wei Sang1,8,*&nbsp;On behalf of the Huaihai Lymphoma Working Group1Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People&rsquo;s Republic of China; 2Department of Quality Management, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People&rsquo;s Republic of China; 3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 4Department of Hematology, Linyi People&rsquo;s Hospital, Linyi, Shandong, People&rsquo;s Republic of China; 5Department of Hematology, The First People&rsquo;s Hospital of Huai&rsquo;an, Huai&rsquo;an, Jiangsu, People&rsquo;s Republic of China; 6Department of Hematology, Tai&rsquo;an Central Hospital, Tai&rsquo;an, Shandong, 271000, People&rsquo;s Republic of China; 7Clinical Research Institute, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People&rsquo;s Republic of China; 8Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, People&rsquo;s Republic of China*These authors contributed equally to this workCorrespondence: Ziyuan Shen, Email sshenzy@126.com Wei Sang, Email xyfylbl515@xzhmu.edu.cnBackground: The aggregate index of systemic inflammation (AISI, calculated as neutrophil count &times; monocyte count &times; platelet count/lymphocyte count) reflects systemic inflammatory status; however, its prognostic role in diffuse large B-cell lymphoma (DLBCL) remains underexplored. This study aimed to investigate the prognostic value of AISI in DLBCL.Methods: A total of 1332 DLBCL patients (median age 62 years; 52.3% male) were included in this study. Patients were stratified based on AISI quartiles, and a cut-off value was determined using restricted cubic splines (RCS) analysis. The associations between AISI and Overall survival (OS) were assessed using Kaplan-Meier analysis and Cox proportional hazards models.Results: Higher AISI levels were associated with adverse clinical features, including advanced Ann Arbor stage, poor performance status, and higher-risk categories of both the IPI and the NCCN-IPI. RCS analysis revealed a nonlinear relationship between AISI and OS, with an inflection point at 261.33. Kaplan-Meier analysis demonstrated that patients with AISI &gt; 261.33 had significantly worse OS compared to those with AISI &le; 261.33 (P = 0.003). Similarly, patients in the Q4 group had poorer OS than those in the lowest two quartiles (Q1-Q2) (P = 0.008). In fully adjusted Cox proportional hazards models (adjusted for age, sex, Ann Arbor stage, LDH, ECOG performance status, BMI, albumin, B symptoms, bone marrow involvement, central nervous system involvement, and liver/spleen involvement), high AISI level (&gt; 261.33) were associated with increased mortality risk (HR = 1.28, 95% CI: 1.04&ndash; 1.57, P = 0.018). Subgroup analyses indicated that the prognostic impact of AISI was particularly evident among patients classified as low risk by conventional prognostic systems.Conclusion: Elevated AISI was associated with inferior OS in DLBCL patients and may potentially serve as a prognostic biomarker.Keywords: aggregate index of systemic inflammation, diffuse large B-cell lymphoma, prognosis, risk stratification

To evaluate the independent and combined effects of metabolic abnormalities and obesity on the risk of knee and hand osteoarthritis (KOA and HOA). Participants from the UK Biobank were classified into four phenotypes: metabolically healthy non-obesity (MHN), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUN), and metabolically unhealthy obesity (MUO). Accelerated failure time (AFT) models were applied to assess the associations of these phenotypes with the risk of KOA and HOA. 389,807 participants (mean 56.4 years, 54.0

To explore the association between serum vitamin D levels and the risk of knee and hip osteoarthritis (KOA and HOA). This study included 295,557 participants (mean 56 years, 53

Background Random glucose (RG) testing provides greater flexibility and convenience, enabling real-time evaluation of blood glucose levels without the need to consider recent dietary intake. This study was aimed at identifying drug targets using the evidence from circulating proteins associated with RG from genome-wide association studies (GWASs) Methods Using two-sample Mendelian randomization (MR) with circulating protein data from nine GWAS, we revealed potential causal relationships between these proteins and RG. A framework of sensitivity analyses was performed to assess the robustness and credibility of the evidence. Results In the cis-protein quantitative trait loci (pQTLs) and the combined cis/trans-pQTLs analyses, 12 and 31 proteins demonstrated causal effects on RG, respectively. Enrichment analysis revealed that proteins prioritized by cis-MR were enriched in the carbohydrate catabolic process, collagen-containing extracellular matrix, and peptidase regulator activity. For all MR-prioritized proteins, pathways were enriched in those related to the maintenance of location, secretory granule lumen, sulfuric ester hydrolase activity, and regulation of lipolysis in adipocytes. Notably, approximately half of these proteins (including PCSK1, PPY, and VWF) were recognized as druggable or existing drug targets. Conclusions This study identified proteins causally linked to RG, emphasizing their potential role in the development of therapeutic interventions for metabolic disorders, particularly those involving glucose regulation.

BACKGROUND AND OBJECTIVES:Funnel plots are the most widely used graphical tool for assessing publication bias (PB) in meta-analyses of superiority trials. However, conventional funnel plots are not directly applicable to noninferiority (NI) or equivalence (EQ) objectives, which are governed by distinct inferential frameworks and may be prone to inverse publication bias (IPB), a tendency for studies with results far from the null to be underreported. This pattern contrasts with classical PB, where studies with results close to the null are more likely to be suppressed. METHODS:We propose trial design-aware funnel plots, a design-aware visualization that incorporates inferential boundaries specific to NI and EQ objectives. By explicitly delineating regions corresponding to key decision thresholds, the proposed plots facilitate visual assessment of where PB or IPB is most likely to arise. For EQ objectives, the plot distinguishes regions supporting EQ, inferiority, and superiority; for NI objectives, it highlights regions reflecting inferiority and nonsuperiority. The framework also accommodates meta-analyses comprising mixtures of NI, EQ, and superiority trials, enabling coherent bias assessment across heterogeneous study designs. RESULTS:We illustrate the proposed approach using three real-world meta-analyses: one EQ-only set, one NI-only set, and one mixed superiority-NI set. These examples demonstrate the flexibility and interpretability of the design-aware funnel plots across commonly encountered trial objectives. CONCLUSION:The trial design-aware funnel plot offers a flexible and intuitive visualization tool for identifying between-study bias in meta-analyses with NI and EQ objectives. It may be particularly valuable for safety outcomes, where the bias mechanisms may differ from classic PB and carry substantial decision-making consequences. Conclusions regarding possible PB, however, may be strongly margin dependent and should be interpreted in light of the prespecified or clinically justified margin. PLAIN LANGUAGE SUMMARY:Standard funnel plots are commonly used to look for PB in meta-analyses, but they were mainly developed for superiority trials and may not work well for NI or EQ objectives. These trial designs use different decision rules, so the types of missing studies may also differ. In particular, some studies with results far from the null may be less likely to be reported, a pattern we describe as inverse PB. We developed a trial design-aware funnel plot that reflects the specific objectives of NI and EQ objectives and helps researchers visually identify where missing studies may occur. We show how this approach works in three real meta-analyses, including EQ-only, NI-only, and mixed design settings. Importantly, conclusions about possible PB may depend strongly on the margin chosen for NI or EQ. This method may help systematic reviewers and decision-makers better understand possible reporting bias in these increasingly common trial designs.

Objective:To analyze the prognostic factors associated with overall survival (OS) in patients diagnosed with immunoglobulin light chain (AL) amyloidosis, with the goal of improving risk stratification and patient management. Methods:A retrospective cohort analysis was conducted on 87 patients diagnosed with AL amyloidosis at the People's Hospital of Ningxia Hui Autonomous Region from January 2016 to December 2023. Demographic, clinical, laboratory data, and survival status were collected. Univariable and multivariable Cox regression analyses were used to identify significant predictors of OS. Kaplan-Meier survival curves and restricted cubic spline (RCS) analysis were employed to evaluate risk stratification. Results:The median overall survival was 22.0 months (95% CI: 15.2-28.8), and the median follow-up duration was 39.0 months (95% CI: 29.2-48.8). Our results revealed that higher bone marrow plasma cell count (BMPCs), myeloma presence, heart failure, and increased fibrinogen degradation products (FDP) were significantly associated with poor survival outcomes. The median survival time for patients with BMPCs >12% was 13 months, compared to 36 months for those with lower BMPCs. Myeloma presence was the strongest predictor of survival, with a median survival of 15 months for those with myeloma versus 36 months for those without. Multivariable analysis identified that myeloma (HR = 2.582, 95% CI: 1.105-6.034, p = 0.029), heart failure (HR = 2.258, 95% CI: 1.098-4.641, p = 0.027), higher BMPCs (HR = 1.018, 95% CI: 1.001-1.035, p = 0.035), and elevated FDP levels (HR = 1.018, 95% CI: 1.004-1.017, p = 0.001) were independent risk factors for death. Conclusion:Elevated BMPCs, concurrent myeloma, heart failure, and increased FDP levels were associated with poor OS of AL amyloidosis patients. These factors could be incorporated into clinical decision-making to better stratify risk and guide treatment strategies for AL amyloidosis patients.

Misused P values and an excessive focus on significance have prompted calls for added robustness metrics. The fragility index (FI), which quantifies how many event status changes are needed to reverse statistical significance, serves as a useful complement. Although FI has been applied in various settings such as dose-finding trials and meta-analyses, its use in survival analysis is limited due to complexities like censoring, variable follow-up, and hazard assumptions. Existing FI adaptations for survival data often reassign individuals across intervention arms in randomized controlled trials (RCTs), diverging from FI's original philosophy and reducing clinical plausibility. We propose a modified FI for survival data (FIS) to assess the robustness of survival analysis results in RCTs. Rather than reassigning individuals between intervention and control groups, FIS preserves the foundational principles of the original FI by quantifying the minimum number of changes in outcome status, either events or censoring, needed to overturn statistical significance. To enhance flexibility and practical utility, we extend FIS to assess fragility in both directions: from statistically significant to nonsignificant results and vice versa. We demonstrate the performance of the proposed method through two real-world cases from RCTs.

Objective To explore the association between periarticular subchondral bone mineral density (sBMD) and the presence and progression of osteoarthritis (OA) knee pain. Methods Participants were recruited from the Osteoarthritis Initiative (OAI). Tibial sBMD at medial and lateral compartments was measured by dual-energy x-ray absorptiometry at 30 or 36 months (baseline) and reassessed at 48 months. Knee pain was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale (range 0-20, with a higher score indicating greater pain) through month 108. Baseline knee pain was categorized as low/no or high (pain score < 5 vs ≥ 5). Pain progression was defined as an increase in WOMAC pain score of ≥ 2 in at least 3 of the 6 follow-up visits. Logistic regression with generalized estimating equations was used to assess associations between sBMD (per SD increase) and knee pain, accounting for within-participant correlation between knees. Results Of 594 participants (mean age 64.1 years; 50.5% male; 1137 knees), 31.6% of knees exhibited higher pain at baseline, and 37.4% demonstrated pain progression during follow-up. Higher medial sBMD and medial-to-lateral sBMD ratio were associated with the progression of knee pain (medial sBMD: odds ratio [OR] 1.50; 95% CI 1.25-1.81; P < 0.001; medial-to-lateral ratio: OR 1.29; 95% CI 1.11-1.49; P = 0.001). Medial-to-lateral sBMD ratio was also associated with the presence of knee pain (OR 1.21; 95% CI 1.05-1.40; P = 0.01). Conclusion Higher medial-to-lateral sBMD ratio was associated with both the presence and progression of knee pain, suggesting that relative subchondral bone distribution may better capture biomechanical loading imbalance related to symptomatic OA than absolute sBMD alone.

Purpose:Alterations in gut microbiota may influence immune response and treatment outcomes in patients with diffuse large B-cell lymphoma (DLBCL). However, the dynamics during anti-CD19 CAR-T cell therapy remain unclear. Methods:We conducted a short-term longitudinal microbiome analysis in DLBCL patients (n=12) undergoing CAR-T cell therapy targeting CD19. Stool samples were collected at baseline, 1 week, and 2 weeks post-infusion. 16S rRNA gene sequencing was used to assess microbial diversity, taxonomic composition, and functional pathways. Correlation analyses were then conducted between microbial taxa and inflammatory biomarkers. Results:Alpha diversity indices showed no statistically significant differences across time points. Beta diversity analysis revealed distinct clustering between baseline and week 1 samples in sPLS-DA, although PERMANOVA did not reach statistical significance. At the phylum level, Bacteroidota abundance significantly increased at week 2 compared with baseline (P = 0.008), accompanied by a marked reduction in the Firmicutes/Bacteroidota ratio. Genus-level heatmap and LEfSe analysis identified enrichment of Parabacteroides, and Prevotella at week 2, whereas baseline samples were enriched in Clostridium sensu stricto 13 and Fusobacterium. Functional prediction indicated that lipoic acid metabolism pathways were significantly upregulated at weeks 1 and 2 compared with baseline (both P < 0.05). Correlation analysis demonstrated that specific bacterial taxa, including Parabacteroides and Prevotella, were positively associated with lymphocyte counts and inversely correlated with C-reactive protein levels. Conclusion:Gut microbiota alterations following CAR-T infusion, characterized by increased Bacteroidota abundance, specific taxonomic shifts, and enhanced lipoic acid metabolism, may provide early microbial signatures for monitoring immune modulation in DLBCL patients.

OBJECTIVES:To systematically evaluate and compare the effectiveness of various toothbrush disinfection methods. METHODS:Four databases were searched for studies published between January 1, 2000, and December 31, 2024. Following risk of bias assessment, meta- and subgroup analyses were performed to estimate the pooled effectiveness of chemical disinfection, home remedies and physical disinfection. RESULTS:Forty-one studies comprising 8 randomized controlled trials (RCTs) and 33 non-RCTs were included. The 3 strategies significantly reduced bacterial load compared to controls (P < .001), with home remedies showing the greatest overall effect with a standardized mean difference (SMD) of -2.97 (95% CI: -4.33 to -1.61). Subgroup analyses revealed that 0.2% chlorhexidine (CHX) demonstrated an extremely large effect (SMD = -3.17, 95% CI: -5.32 to -1.02; P < .001), while 50% white vinegar treatment also demonstrated extremely large effects (SMD = -2.52, 95% CI: -4.50 to -0.55; P < .001). Ultraviolet (UV)-based disinfection exhibited statistically significant effects (SMD = -1.79, 95% CI: -3.52 to -0.07; P < .001). Despite overall effectiveness, substantial heterogeneity (I >75%) and 95% prediction intervals (PIs) that included zero were observed across studies. Overall, the certainty of evidence was deemed very low. CONCLUSIONS:The 3 strategies effectively reduce toothbrush contamination. CHX remains the reference standard, while home remedies and physical disinfection show promise as accessible alternatives. However, due to high heterogeneity and risk of bias across studies, these finding should be interpreted with caution. Future research requires high-quality, standardized RCTs to confirm clinical efficacy and optimize protocols.

Introduction:The weighted mean difference (WMD) has long been used in evidence syntheses involving continuous outcomes. However, it is sometimes applied interchangeably with the mean difference (MD) despite their conceptual distinction: the WMD is intended solely for pooled estimates across studies, not for individual study results. Misuse of WMD can lead to ambiguity in reporting and interpretation, yet empirical evidence on their prevalence and patterns in published systematic reviews and meta-analyses (SRMAs) remains limited.Methods:We conducted a meta-epidemiological study of SRMAs reporting continuous outcomes, published in The BMJ during 2 periods: 2002-2007 and 2020-2025. Each article was evaluated to determine whether the WMD was reported, whether its use was appropriate, and the rationale for each assessment. Two authors independently performed the evaluations, and any disagreements were resolved through discussion.Results:In the earlier study period, misuse of the term WMD was widespread, with many SRMAs employing it interchangeably with the MD without clear justification. Over time, the frequency of such misuse decreased, coinciding with the broader adoption of reporting guidelines and increased methodological rigor. Nonetheless, inappropriate applications of WMD persist in more recent publications.Conclusions:Persistent inconsistencies in WMD use reveal gaps in methodological understanding and reporting practice. Ongoing efforts to refine guidance and promote evidence synthesis literacy are essential to improve the rigor and transparency of SRMAs.

Systematic reviews and meta-analyses are essential tools for synthesizing evidence from multiple studies. Recently, trial sequential analyses (TSAs) have gained popularity as a component of meta-analyses, helping researchers dynamically monitor evidence as new studies are incorporated. This article introduces a meta-epidemiological study aimed at evaluating the reproducibility of TSAs within systematic reviews published in 2023. Two independent investigators assessed and reproduced the main TSA for each included systematic review. Our search in PubMed yielded a convenience sample of 98 systematic reviews. Only 28% (27/98) of the included TSAs provided sufficient data to calculate the required information size, an essential element for assessing statistical power and conducting TSAs. Among these, 81% (22/27) provided the necessary data to determine decision boundaries and Z-curves in TSAs. Overall, full reproducibility was achieved for only 13% (13/98) of TSAs. Specifically, for binary outcomes, 65% (47/72) of TSAs failed to report event rates in control groups, and 44% (32/72) did not report relative risk reductions. For continuous outcomes, 53% (17/32) failed to report minimally relevant differences, and 72% (23/32) did not report variances. These elements are crucial for TSA reproducibility. Moreover, the reproducibility of TSAs was associated with journal impact factors and adherence to the PRISMA guidelines. A collective effort is needed from systematic review authors, peer reviewers, and journal editors to improve the reproducibility of TSAs.

This study aimed to comprehensively analyze the epidemiological trends and global burden of hematologic malignancies (HM) from 1990 to 2021 and to project trends up to the year 2030. Using data from the Global Burden of Disease (GBD) Study 2021, we analyzed the age-standardized rates (ASRs) and the trends of HM from 1990 to 2021. Decomposition analysis was used to assess the contributions of population-level determinants. Nordpred age-period-cohort (APC) models were developed to forecast the burden of HM. Globally, the prevalence of HM increased significantly from 1990 to 2021, from 2343.58 thousand to 5391.05 thousand cases. The ASIR for leukemia, multiple myeloma (MM), Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) were 5.6, 1.7, 0.8, and 7.1 per 100,000 population in 2021, respectively. From 1990 to 2021, the ASPR of leukemia increased despite decreases in ASIR, ASMR, and ASDR. Both MM and NHL displayed rising ASIR and ASPR, with MM also showing an increase in ASMR. HL exhibited declines across all metrics. Peak incidences of leukemia, MM, HL, and NHL in 2021 were most common in the age groups 0–4, 25–34, 65–74, and 70–74 years, respectively. Decomposition analysis highlighted that population growth contributed the most to the increase in ASDR for NHL. By 2030, ASDR for leukemia, HL, and NHL are projected to decrease, whereas ASDR for MM is expected to rise, particularly among males. The global burden of HM has undergone significant changes, with diverse trends in the incidence and mortality rates across different types.

RATIONALE:Zero-event counts are common in clinical studies, particularly when assessing rare adverse events. These occurrences can result from low event rates, short follow-up periods, and small sample sizes. When both intervention and control groups report zero events in a clinical trial, the study is referred to as a double-zero-event study, which presents methodological challenges for evidence synthesis. There has been ongoing debate about whether these studies should be excluded from evidence synthesis, as traditional two-stage meta-analysis methods may not estimate an effect size for them. Recent research suggests that these studies may still contain valuable clinical and statistical information. AIMS AND OBJECTIVES:This study examines the role of double-zero-event studies from the perspective of the fragility index (FI), a popular metric for assessing the robustness of clinical results. We aim to determine how including or excluding double-zero-event studies affects FI derivations in meta-analyses. METHODS:We conducted an illustrative case study to demonstrate how double-zero-event studies can impact FI derivations. Additionally, we performed a large-scale analysis of 12,184 Cochrane meta-analyses involving zero-event studies to assess the prevalence and effect of double-zero-event studies on FI calculations. RESULTS:Our analysis revealed that FI derivations in 6608 (54.2%) of these meta-analyses involved double-zero-event studies. Excluding double-zero-event studies could lead to artificially inflated FI values, potentially misrepresenting the results as more robust than they are. CONCLUSIONS:We advocate for retaining double-zero-event studies in meta-analyses and emphasise the importance of carefully considering their role in FI assessments. Including these studies ensures a more accurate evaluation of the robustness of clinical results in evidence synthesis.