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Zhang H, Pu J, Deng S, Roychoudhury S, Chu H, Robinson D. Study duration prediction for clinical trials with time-to-event endpoints accounting for heterogeneous population. J Biopharm Stat 2025:1-16. [PMID: 40253618 DOI: 10.1080/10543406.2025.2489294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 02/10/2025] [Indexed: 04/22/2025]
Abstract
In the era of precision medicine, more and more clinical trials are now driven or guided by biomarkers, which are patient characteristics objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. With the overarching objective to optimize and personalize disease management, biomarker-guided clinical trials increase the efficiency by appropriately utilizing prognostic or predictive biomarkers in the design. However, the efficiency gain is often not quantitatively compared to the traditional all-comers design, in which a faster enrollment rate is expected (e.g. due to no restriction to biomarker positive patients) potentially leading to a shorter duration. To accurately predict biomarker-guided trial duration, we propose a general framework using mixture distributions accounting for heterogeneous population. Extensive simulations are performed to evaluate the impact of heterogeneous population and the dynamics of biomarker characteristics and disease on the study duration. Several influential parameters including median survival time, enrollment rate, biomarker prevalence and effect size are identified. Re-assessments of two publicly available trials are conducted to empirically validate the prediction accuracy and to demonstrate the practical utility.
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Affiliation(s)
- Hong Zhang
- Global Biometrics and Data Management, Pfizer Inc., New York, USA
| | - Jie Pu
- Global Biometrics and Data Management, Pfizer Inc., New York, USA
| | - Shibing Deng
- Global Biometrics and Data Management, Pfizer Inc., New York, USA
| | | | - Haitao Chu
- Global Biometrics and Data Management, Pfizer Inc., New York, USA
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, USA
| | - Douglas Robinson
- Global Biometrics and Data Management, Pfizer Inc., New York, USA
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Garzón Ruiz JP, Giraldo Bejarano E, Mercado Díaz MA, Pardo Turriago R. Anticoagulation in ECMO: Target Values to Reduce Hemorrhagic Complications in Adults. A Retrospective Cohort Study. ASAIO J 2025:00002480-990000000-00661. [PMID: 40094210 DOI: 10.1097/mat.0000000000002415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
The 2021 Adult and Pediatric Anticoagulation Guidelines for patients on extracorporeal membrane oxygenation (ECMO) recommend a target partial thromboplastin time (PTT) between 60 and 85 seconds when unfractionated heparin (UFH) is administered as an anticoagulant. However, institutions may develop their own protocols in the absence of solid evidence regarding patient anticoagulation during ECMO support. We aimed to determine the association between maintenance anticoagulation with different PTT ranges among patients receiving UFH or no anticoagulation therapy and the occurrence of hemorrhagic complications in adults receiving ECMO support. We conducted a prospective cohort study that included 277 adults on ECMO support. Kaplan-Meier curves were used to compare the time-dependent risk of hemorrhagic events. The association was estimated using the hazard ratio, and the risk was estimated using the multivariate Cox proportional hazards model adjusted for covariates. The time-dependent risk of hemorrhagic events during ECMO support was 2.97-fold higher in patients with a PTT greater than 70 than in patients under no UFH therapy (95% confidence interval [CI]: 1.53-5.77; p = 0.001). An association was observed between target PTT and hemorrhagic complications, with the risk of hemorrhagic complications being higher when maintaining PTT values greater than 70 seconds during ECMO support.
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Gonzalez MR, Lim PL, Chen AF, Melnic CM, Bedair HS. Comparing Rates of Minimal Clinically Important Difference Between Manual and Robotic-Assisted Total Knee Arthroplasty. J Arthroplasty 2025; 40:637-643. [PMID: 39218238 DOI: 10.1016/j.arth.2024.08.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Differences in patient-reported outcome measures (PROMs) between manual total knee arthroplasty (mTKA) and robotic-assisted TKA (rTKA) have not been adequately assessed. We compared the minimal clinically important difference (MCID) for improvement (MCID-I) and worsening (MCID-W) between mTKA and rTKA patients. METHODS Patients who underwent primary TKA (874 mTKA and 439 rTKA) with complete preoperative and 1-year postoperative PROMs were retrospectively identified using a multihospital joint arthroplasty registry. Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS PF-10a), PROMIS Global - Physical, or Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form were collected. The MCID-I, MCID-W, and "no significant change" rates were calculated using distribution-based methods. Propensity score matching was performed to control for confounding. RESULTS Similar 90-day pulmonary embolism (P = 0.26), deep venous thrombosis (P = 0.67), and emergency department visit (P = 0.35) rates were found. The 90-day readmission rate for mTKA was 1.7 and 3.4% for rTKA (P = 0.08), and the overall revision rates were 2.2% for mTKA and 0.7% for rTKA (P = 0.07). Revision-free survival was 99% at one and 2 years for both groups (P = 0.65 and P = 0.43, respectively). There were no differences in the proportion of patients achieving MCID-I or MCID-W for PROMIS PF-10a, PROMIS Global - Physical, or Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form. The MCID-I for PROMIS PF-10a was achieved in 65.5 and 62.2% of patients who had mTKA and rTKA, respectively (P = 0.32). CONCLUSIONS Our study demonstrated similar complication rates and MCID-I and MCID-W attainment rates between mTKA and rTKA patients. Future studies should assess MCID attainment rates in the long term and in larger cohorts comparing mTKA and rTKA.
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Affiliation(s)
- Marcos R Gonzalez
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Perry L Lim
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Orthopaedic Surgery, Newton-Wellesley Hospital, Newton, Massachusetts
| | - Antonia F Chen
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Boston, Massachusetts
| | - Christopher M Melnic
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Orthopaedic Surgery, Newton-Wellesley Hospital, Newton, Massachusetts
| | - Hany S Bedair
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Orthopaedic Surgery, Newton-Wellesley Hospital, Newton, Massachusetts
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Coory M, Jordan SJ. Statistical noise in PD-(L)1 inhibitor trials: unraveling the durable-responder effect. J Clin Epidemiol 2025; 177:111589. [PMID: 39505054 DOI: 10.1016/j.jclinepi.2024.111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 10/14/2024] [Accepted: 10/24/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND AND OBJECTIVES Programmed-death-1/ligand-1 inhibitors (PD-1/L1is) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically relevant) percentage of patients (5%-20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1 is have obtained statistically significant results, leading to marketing approval for some cancer indications but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer but not others; or subtle differences in trial design. To investigate a less-explored hypothesis-the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomized controlled trials (RCTs) that report randomly variable results. STUDY DESIGN Employing simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple prespecified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm. RESULTS When the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0-suggesting potential harm when none exists. CONCLUSION This article adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially, unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm. PLAIN LANGUAGE SUMMARY Programmed-death-1/ligand-1 (PD-1(L)1) inhibitors are crucial cancer treatments, with global spending expected to surpass $75 billion by 2026. Multiple versions of these medicines are available, all designed to boost the immune system to fight cancer. We would expect them all to work similarly, but clinical trials show mixed results-some seem effective for certain cancers but not others, without a clear pattern. This article uses simulations (virtual trials) to suggest that these inconsistent results may be due to chance, caused by a small group of patients who respond very well to the treatment. Larger trials or specific analysis methods could help reduce the chance effects and provide more robust data for clinician and patient decision-making.
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Affiliation(s)
- Michael Coory
- Mater Research Institute, The University of Queensland, Level 3, Aubigny Place, South Brisbane, Queensland, Australia.
| | - Susan J Jordan
- School of Population Health, The University of Queensland, Brisbane, Queensland, Australia
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Smith MJ, Merle JL, Baker-Ericzén M, Sherwood K, Bornheimer LA, Ross B, Harrington M, Sharma A, Brown C, Gordon T(TJ, Telfer D, Reese J, Hirst J, Oulvey EA, Dignadice V, Williams ED, Magaña S, Hume K, Sung C, Burke-Miller JK, Smith JD. A type 1 hybrid multi-site randomized controlled trial protocol for evaluating virtual interview training among autistic transition-age youth. Contemp Clin Trials Commun 2024; 42:101384. [PMID: 39525564 PMCID: PMC11550008 DOI: 10.1016/j.conctc.2024.101384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/09/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024] Open
Abstract
A number of policies mandate that autistic transition-age youth receive employment services to prepare for the workforce before high school graduation. A key limitation to these services is the job interview component, which relies on non-standardized, resource-intensive, staff-led role-plays to help autistic transition-age youth improve their interview skills. The autism community has called for better job interview preparation. To address this gap in services, our team, collaborated with the autism community to adapt the intervention, Virtual Reality Job Interview Training (VR-JIT; effective among adults with serious mental illness), into Virtual Interview Training for Transition Age Youth (VIT-TAY). This adapted intervention was tailored to meet the needs of autistic transition age youth while maintaining the core components of VR-JIT (i.e., an online job interview simulator with four levels of automated feedback and e-learning content). A pilot randomized controlled trial (RCT) demonstrated VIT-TAY's feasibility and initial effectiveness at improving job interview skills, reducing anxiety, and increasing employment rates within six months when added to transition services or pre-employment transition services (Pre-ETS). Thus, the overarching goal of this Hybrid Type 1 effectiveness-implementation study protocol is to conduct a fully-powered RCT of VIT-TAY across 16 schools in various geographical locations. Our specific aims are to 1) Evaluate whether Pre-ETS (or transition services) with VIT-TAY, as compared to Pre-ETS (or transition services) with an active control intervention (i.e., job interview didactics/e-learning with a series of 3-5 min videos of employed autistic adults talking about their career pathways) enhances employment outcomes; 2) Evaluate mechanisms of employment by nine months post-randomization; and 3) Conduct a multilevel, mixed-method process evaluation of the initial implementation of VIT-TAY across settings (e.g., acceptability, feasibility, and barriers and facilitators of implementation).
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Affiliation(s)
- Matthew J. Smith
- University of Michigan, School of Social Work, Ann Arbor, MI, USA
| | - James L. Merle
- University of Utah Spencer Fox Eccles School of Medicine, Department of Population Health Sciences, Division of Health System Innovation and Research, Salt Lake City, UT, USA
| | - Mary Baker-Ericzén
- San Diego State University, Department of Administration, Rehabilitation and Post-Secondary Education, San Diego, CA, USA
| | - Kari Sherwood
- University of Michigan, School of Social Work, Ann Arbor, MI, USA
- University of Michigan Department of Psychology, Ann Arbor, MI, USA
| | - Lindsay A. Bornheimer
- University of Michigan, School of Social Work, Ann Arbor, MI, USA
- Michigan Medicine Department of Psychiatry, Ann Arbor, MI, USA
| | - Brittany Ross
- University of Michigan, School of Social Work, Ann Arbor, MI, USA
| | | | - Apara Sharma
- University of Michigan, School of Social Work, Ann Arbor, MI, USA
| | | | - Timotheus (TJ) Gordon
- Autism Self-Advocate and Institute on Disability and Human Development at the University of Illinois, Chicago, IL, USA
| | - David Telfer
- Independent Autism Self-Advocate, Warren, RI, USA
| | - Jocelyn Reese
- Lincoln Park Mixter Institute, Lincoln Park, MI, USA
| | - Jennifer Hirst
- Michigan Rehabilitation Services, Michigan Department of Labor & Economic Opportunity, Lansing, MI, USA
| | - Eugene A. Oulvey
- Department of Rehabilitation Services, Illinois Department of Human Services, Springfield, IL, USA
| | | | | | - Sandra Magaña
- University of Texas, School of Social work, Austin, TX, USA
| | - Kara Hume
- University of North Carolina, School of Education, Chapel Hill, NC, USA
| | - Connie Sung
- Michigan State University, East Lansing, MI, USA
| | | | - Justin D. Smith
- University of Utah Spencer Fox Eccles School of Medicine, Department of Population Health Sciences, Division of Health System Innovation and Research, Salt Lake City, UT, USA
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Idasiak A, Ziółkowska B, Rajczykowski M, Galwas K, Dębosz-Suwińska I, Zeman M, Mrochem-Kwarciak J, Suwiński R. Randomized clinical trial on accelerated preoperative hyperfractionated radiotherapy versus preoperative hyperfractionated radio-chemotherapy in locally advanced rectal cancer. Br J Radiol 2024; 97:1879-1889. [PMID: 39240387 DOI: 10.1093/bjr/tqae176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 04/18/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024] Open
Abstract
OBJECTIVES The aim of this study was to compare pathological response rates after preoperative hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) versus preoperative hyperfractionated radiotherapy (HART) in patients with resectable rectal cancer. METHODS Patients with T2/N+ or T3/any N rectal cancer were randomized either to HART twice a day (28 fractions of 1.5 Gy) to total dose 42 Gy or to HART-CT. Tumour regression grade was postoperatively assessed according to the 4-point scale as recommended by the American Joint Committee on Cancer (AJCC). The secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity of preoperative treatment, locoregional, and distant failure rates. There were 187 patients eligible for analysis: 95 in HART and 92 in the HART-CT. Median follow-up was 5.6 years. RESULTS The analysis demonstrated a significantly higher chance of achieving pathologic complete response in HART-CT arm: complete response was achieved in 4/95, 4% (HART) and 11/92, 12% (HART-CT) (P = .045). The differences in OS and DFS, while tending to favour HART-CT, were not significant: OS (P = .13, hazard ratio [HR] = 0.82, 95% CI, 0.63-1.06) and DFS (P = .32; HR = 0.88, 95% CI, 0.69-1.13). The locoregional failure and distant metastases rates did not statistically differ between the trial arms. The rate of late complications was similar (P = .51), grade 3+ being 8% versus 11% in the HART/HART-CT group, respectively. CONCLUSIONS The hyperfractionated preoperative radiotherapy with concurrent 5-Fu-based chemotherapy (HART-CT) improved pathological response rate compared to HART. This translated into favourable OS and DFS in HART-CT, but the differences did not reach the threshold for significance. ADVANCES IN KNOWLEDGE A new hyperfractionated chemo-RT scheme is proposed. Histopathological major response (TRG 0-1) is associated with better clinical outcome.
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Affiliation(s)
- Adam Idasiak
- IInd Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Barbara Ziółkowska
- IInd Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Marcin Rajczykowski
- IInd Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Katarzyna Galwas
- IInd Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Iwona Dębosz-Suwińska
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Marcin Zeman
- The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Jolanta Mrochem-Kwarciak
- Analytics and Clinical Biochemistry Department, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
| | - Rafał Suwiński
- IInd Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, 44-100 Gliwice, Poland
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Burdon AJ, Baird RD, Jaki T. Adaptive enrichment trial designs using joint modelling of longitudinal and time-to-event data. Stat Methods Med Res 2024; 33:2098-2114. [PMID: 39410878 DOI: 10.1177/09622802241287711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
Adaptive enrichment allows for pre-defined patient subgroups of interest to be investigated throughout the course of a clinical trial. These designs have gained attention in recent years because of their potential to shorten the trial's duration and identify effective therapies tailored to specific patient groups. We describe enrichment trials which consider long-term time-to-event outcomes but also incorporate additional short-term information from routinely collected longitudinal biomarkers. These methods are suitable for use in the setting where the trajectory of the biomarker may differ between subgroups and it is believed that the long-term endpoint is influenced by treatment, subgroup and biomarker. Methods are most promising when the majority of patients have biomarker measurements for at least two time points. We implement joint modelling of longitudinal and time-to-event data to define subgroup selection and stopping criteria and we show that the familywise error rate is protected in the strong sense. To assess the results, we perform a simulation study and find that, compared to the study where longitudinal biomarker observations are ignored, incorporating biomarker information leads to increases in power and the (sub)population which truly benefits from the experimental treatment being enriched with higher probability at the interim analysis. The investigations are motivated by a trial for the treatment of metastatic breast cancer and the parameter values for the simulation study are informed using real-world data where repeated circulating tumour DNA measurements and HER2 statuses are available for each patient and are used as our longitudinal data and subgroup identifiers, respectively.
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Affiliation(s)
| | - Richard D Baird
- Department of Oncology, Cancer Research UK, Cambridge Centre, University of Cambridge, Cambridge, UK
| | - Thomas Jaki
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
- Department of Machine Learning and Data Science, University of Regensburg, Regensburg, Bayern, Germany
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Bignotto M, Bianco E, Centofanti L, Russo A, Dei Cas M, Zermiani P, Morano C, Samartin F, Bertolini E, Bifari F, Berra C, Zuin M, Paroni R, Battezzati PM, Folli F. Synergistic effects of glucose tolerance and BMI on cardiovascular events and all-cause mortality in a healthy population: CA.ME.LI.A study 7 years follow-up. Am J Physiol Endocrinol Metab 2024; 327:E498-E511. [PMID: 39196799 PMCID: PMC11482241 DOI: 10.1152/ajpendo.00181.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/08/2024] [Accepted: 08/20/2024] [Indexed: 08/30/2024]
Abstract
The CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) epidemiological study was conducted in Abbiategrasso (Milan, Italy) to identify risk factors for metabolic and cardiovascular disease in an apparently healthy population of northern Italy. The population (n = 2,545, 1,251 men, 1,254 women) was stratified according to body mass index [normal body weight (NBW): <25 kg/m2; overweight-obese (OWO): ≥25 kg/m2] and according to fasting blood glucose [normal fasting glucose: <100 mg/dL; impaired fasting glucose (IFG): 100-125 mg/dL; diabetes mellitus (DM): ≥126 mg/dL]. The incidence of cardiovascular (CV) events and overall mortality were studied by the Kaplan-Meier method using the log rank test. Univariate analysis was conducted with time-dependent Cox models. During the 7-yr follow-up period, 80 deaths and 149 CV events occurred. IFG [hazard ratio (HR): 2.81; confidence interval (CI): 1.37-5.77; P = 0.005], DM (HR: 4.88; CI: 1.47-16; P = 0.010), or OWO (HR: 2.78; CI:1.68-4.59; P < 0.001) all produced significant increases in CV events and deaths. In the combination IFG/OWO (HR: 5.51; CI: 3.34-9.08; P < 0.001), there was an apparent additive effect of the two conditions, whereas in the combination DM/OWO (HR: 12.71; CI: 7.48-22; P < 0.001), there was an apparent multiplicative effect on the risk for CV events and deaths. In males, the DM/NBW group had a higher incidence of cardiovascular events and deaths than the IFG/OWO group. In contrast, in females, the IFG/OWO group had a higher incidence of cardiovascular events and deaths than the DM/NBW group. In women, there was a greater incidence of CV events in the IFG/OWO group (HR: 6.23; CI: 2.88-13; P < 0.001) than in men in the same group (HR: 4.27; CI: 2.15-8.47; P < 0.001). Consistent with these data, also all-cause mortality was progressively increased by IFG/DM and OWO, with an apparently exponential effect in the combination DM/OWO (HR: 11.78; CI: 6.11-23; P < 0.001). IFG/DM and OWO, alone or in combination, had major effects in increasing mortality for all causes and CV events. The relative contributions of hyperglycemia and overweight/obesity on cardiovascular events and deaths were apparently, to a certain extent, sex dependent. Females were more affected by overweight/obesity either alone or combined with IFG, as compared with males.NEW & NOTEWORTHY For the first time, the combined effects of glucose tolerance and BMI have been investigated in an apparently healthy large population sample of a city in the north of Italy. We found that there are synergistic effects of glucose levels with BMI to increase not only cardiovascular events and deaths but also cancer-related deaths and all-cause mortality.
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Affiliation(s)
- Monica Bignotto
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Elena Bianco
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Medicine and Liver Unit, ASST Santi Paolo e Carlo, Milan, Italy
| | - Lucia Centofanti
- Clinical Biochemistry and Mass Spectrometry Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Antonio Russo
- Epidemiology Unit, Agency for Health Protection of the Metropolitan City of Milan, Milan, Italy
| | - Michele Dei Cas
- Clinical Biochemistry and Mass Spectrometry Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paola Zermiani
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Camillo Morano
- Clinical Biochemistry and Mass Spectrometry Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Federica Samartin
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Medicine and Liver Unit, ASST Santi Paolo e Carlo, Milan, Italy
| | | | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA, Segrate, Italy
| | - Cesare Berra
- Dipartimento Endocrino-Metabolico, IRCCS MultiMedica, Milano, Italy
| | - Massimo Zuin
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Rita Paroni
- Clinical Biochemistry and Mass Spectrometry Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Pier Maria Battezzati
- Liver and Gastroenterology Unit, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Medicine and Liver Unit, ASST Santi Paolo e Carlo, Milan, Italy
| | - Franco Folli
- Departmental Unit for Diabetes and Metabolic Diseases, ASST Santi Paolo e Carlo, Milan, Italy
- Departmental Unit for Diabetes and Metabolic Diseases, ASST Santi Paolo e Carlo, Milan, Italy
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Bin-Alamer O, Abou-Al-Shaar H, Peker S, Samanci Y, Pelcher I, Begley S, Goenka A, Schulder M, Tourigny JN, Mathieu D, Hamel A, Briggs RG, Yu C, Zada G, Giannotta SL, Speckter H, Palque S, Tripathi M, Kumar S, Kaur R, Kumar N, Rogowski B, Shepard MJ, Johnson BA, Trifiletti DM, Warnick RE, Dayawansa S, Mashiach E, Vasconcellos FDN, Bernstein K, Schnurman Z, Alzate J, Kondziolka D, Sheehan JP. Vestibular Schwannoma International Study of Active Surveillance Versus Stereotactic Radiosurgery: The VISAS Study. Int J Radiat Oncol Biol Phys 2024; 120:454-464. [PMID: 38588868 DOI: 10.1016/j.ijrobp.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/23/2024] [Accepted: 04/02/2024] [Indexed: 04/10/2024]
Abstract
PURPOSE The present study assesses the safety and efficacy of stereotactic radiosurgery (SRS) versus observation for Koos grade 1 and 2 vestibular schwannoma (VS), benign tumors affecting hearing and neurological function. METHODS AND MATERIALS This multicenter study analyzed data from Koos grade 1 and 2 VS patients managed with SRS (SRS group) or observation (observation group). Propensity score matching balanced patient demographics, tumor volume, and audiometry. Outcomes measured were tumor control, serviceable hearing preservation, and neurological outcomes. RESULTS In 125 matched patients in each group with a 36-month median follow-up (P = .49), SRS yielded superior 5- and 10-year tumor control rates (99% CI, 97.1%-100%, and 91.9% CI, 79.4%-100%) versus observation (45.8% CI, 36.8%-57.2%, and 22% CI, 13.2%-36.7%; P < .001). Serviceable hearing preservation rates at 5 and 9 years were comparable (SRS 60.4% CI, 49.9%-73%, vs observation 51.4% CI, 41.3%-63.9%, and SRS 27% CI, 14.5%-50.5%, vs observation 30% CI, 17.2%-52.2%; P = .53). SRS were associated with lower odds of tinnitus (OR = 0.39, P = .01), vestibular dysfunction (OR = 0.11, P = .004), and any cranial nerve palsy (OR = 0.36, P = .003), with no change in cranial nerves 5 or 7 (P > .05). Composite endpoints of tumor progression and/or any of the previous outcomes showed significant lower odds associated with SRS compared with observation alone (P < .001). CONCLUSIONS SRS management in matched cohorts of Koos grade 1 and 2 VS patients demonstrated superior tumor control, comparable hearing preservation rates, and significantly lower odds of experiencing neurological deficits. These findings delineate the safety and efficacy of SRS in the management of this patient population.
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Affiliation(s)
- Othman Bin-Alamer
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Hussam Abou-Al-Shaar
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Selcuk Peker
- Department of Neurosurgery, Koc University School of Medicine, Istanbul, Turkey
| | - Yavuz Samanci
- Department of Neurosurgery, Koc University School of Medicine, Istanbul, Turkey
| | - Isabelle Pelcher
- Department of Neurosurgery, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Sabrina Begley
- Department of Neurosurgery, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Anuj Goenka
- Department of Neurosurgery, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Michael Schulder
- Department of Neurosurgery, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Jean-Nicolas Tourigny
- Department of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Quebec, Canada
| | - David Mathieu
- Department of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Quebec, Canada
| | - Andréanne Hamel
- Department of Neurosurgery, Université de Sherbrooke, Centre de recherche du CHUS, Sherbrooke, Quebec, Canada
| | - Robert G Briggs
- Department of Neurosurgery, University of Southern California, Los Angeles, California
| | - Cheng Yu
- Department of Neurosurgery, University of Southern California, Los Angeles, California
| | - Gabriel Zada
- Department of Neurosurgery, University of Southern California, Los Angeles, California
| | - Steven L Giannotta
- Department of Neurosurgery, University of Southern California, Los Angeles, California
| | - Herwin Speckter
- Dominican Gamma Knife Center and Radiology Department, CEDIMAT, Santo Domingo, Dominican Republic
| | - Sarai Palque
- Dominican Gamma Knife Center and Radiology Department, CEDIMAT, Santo Domingo, Dominican Republic
| | - Manjul Tripathi
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Saurabh Kumar
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rupinder Kaur
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Narendra Kumar
- Department of Neurosurgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Brandon Rogowski
- Drexel University School of Medicine, Philadelphia, Pennsylvania
| | - Matthew J Shepard
- Department of Neurosurgery, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Bryan A Johnson
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida
| | | | - Ronald E Warnick
- Gamma Knife Center, Jewish Hospital, Mayfield Clinic, Cincinnati, Ohio
| | - Samantha Dayawansa
- Department of Neurosurgery, University of Virginia, Charlottesville, Virginia
| | - Elad Mashiach
- Department of Neurosurgery, NYU Langone, Manhattan, New York
| | | | | | - Zane Schnurman
- Department of Neurosurgery, NYU Langone, Manhattan, New York
| | - Juan Alzate
- Department of Neurosurgery, NYU Langone, Manhattan, New York
| | | | - Jason P Sheehan
- Department of Neurosurgery, University of Virginia, Charlottesville, Virginia.
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10
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Hsu WC, Crowley A, Parzynski CS. The impact of different censoring methods for analyzing survival using real-world data with linked mortality information: a simulation study. BMC Med Res Methodol 2024; 24:203. [PMID: 39272007 PMCID: PMC11395225 DOI: 10.1186/s12874-024-02313-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Evaluating outcome reliability is critical in real-world evidence studies. Overall survival is a common outcome in these studies; however, its capture in real-world data (RWD) sources is often incomplete and supplemented with linked mortality information from external sources. Conflicting recommendations exist for censoring overall survival in real-world evidence studies. This simulation study aimed to understand the impact of different censoring methods on estimating median survival and log hazard ratios when external mortality information is partially captured. METHODS We used Monte Carlo simulation to emulate a non-randomized comparative effectiveness study of two treatments with RWD from electronic health records and linked external mortality data. We simulated the time to death, the time to last database activity, and the time to data cutoff. Death events after the last database activity were attributed to linked external mortality data and randomly set to missing to reflect the sensitivity of contemporary real-world data sources. Two censoring schemes were evaluated: (1) censoring at the last activity date and (2) censoring at the end of data availability (data cutoff) without an observed death. We assessed the performance of each method in estimating median survival and log hazard ratios using bias, coverage, variance, and rejection rate under varying amounts of incomplete mortality information and varying treatment effects, length of follow-up, and sample size. RESULTS When mortality information was fully captured, median survival estimates were unbiased when censoring at data cutoff and underestimated when censoring at the last activity. When linked mortality information was missing, censoring at the last activity date underestimated the median survival, while censoring at the data cutoff overestimated it. As missing linked mortality information increased, bias decreased when censoring at the last activity date and increased when censoring at data cutoff. CONCLUSIONS Researchers should consider the completeness of linked external mortality information when choosing how to censor the analysis of overall survival using RWD. Substantial bias in median survival estimates can occur if an inappropriate censoring scheme is selected. We advocate for RWD providers to perform validation studies of their mortality data and publish their findings to inform methodological decisions better.
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Affiliation(s)
- Wei-Chun Hsu
- Genesis Research Group, 111 River St, Ste 1120, Hoboken, NJ, 07030, USA
| | - Aaron Crowley
- Genesis Research Group, 111 River St, Ste 1120, Hoboken, NJ, 07030, USA
| | - Craig S Parzynski
- Genesis Research Group, 111 River St, Ste 1120, Hoboken, NJ, 07030, USA.
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11
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Dormuth I, Pauly M, Rauch G, Herrmann C. Sample Size Calculation Under Nonproportional Hazards Using Average Hazard Ratios. Biom J 2024; 66:e202300271. [PMID: 39132909 DOI: 10.1002/bimj.202300271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 03/18/2024] [Accepted: 04/28/2024] [Indexed: 08/13/2024]
Abstract
Many clinical trials assess time-to-event endpoints. To describe the difference between groups in terms of time to event, we often employ hazard ratios. However, the hazard ratio is only informative in the case of proportional hazards (PHs) over time. There exist many other effect measures that do not require PHs. One of them is the average hazard ratio (AHR). Its core idea is to utilize a time-dependent weighting function that accounts for time variation. Though propagated in methodological research papers, the AHR is rarely used in practice. To facilitate its application, we unfold approaches for sample size calculation of an AHR test. We assess the reliability of the sample size calculation by extensive simulation studies covering various survival and censoring distributions with proportional as well as nonproportional hazards (N-PHs). The findings suggest that a simulation-based sample size calculation approach can be useful for designing clinical trials with N-PHs. Using the AHR can result in increased statistical power to detect differences between groups with more efficient sample sizes.
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Affiliation(s)
- Ina Dormuth
- Department of Statistics, TU Dortmund University, Dortmund, Germany
| | - Markus Pauly
- Department of Statistics, TU Dortmund University, Dortmund, Germany
- Research Center Trustworthy Data Science and Security, UA Ruhr, Dortmund, Germany
| | - Geraldine Rauch
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Technical University Berlin, Berlin, Germany
| | - Carolin Herrmann
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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12
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Sharma P, Phadnis MA. Stochastic curtailment tests for phase II trial with time-to-event outcome using the concept of relative time in the case of non-proportional hazards. J Biopharm Stat 2024; 34:596-611. [PMID: 37574976 DOI: 10.1080/10543406.2023.2244056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/15/2023] [Indexed: 08/15/2023]
Abstract
As part of the drug development process, interim analysis is frequently used to design efficient phase II clinical trials. A stochastic curtailment framework is often deployed wherein a decision to continue or curtail the trial is taken at each interim look based on the likelihood of observing a positive or negative treatment effect if the trial were to continue to its anticipated end. Thus, curtailment can take place due to evidence of early efficacy or futility. Traditionally, in the case of time-to-event endpoints, interim monitoring is conducted in a two-arm clinical trial using the log-rank test, often with the assumption of proportional hazards. However, when this is violated, the log-rank test may not be appropriate, resulting in loss of power and subsequently inaccurate sample sizes. In this paper, we propose stochastic curtailment methods for two-arm phase II trial with the flexibility to allow non-proportional hazards. The proposed methods are built utilizing the concept of relative time assuming that the survival times in the two treatment arms follow two different Weibull distributions. Three methods - conditional power, predictive power and Bayesian predictive probability - are discussed along with corresponding sample size calculations. The monitoring strategy is discussed with a real-life example.
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Affiliation(s)
- Palash Sharma
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Milind A Phadnis
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
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13
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Gonzalez MR, Acosta JI, Clunk MJ, Bedi ADS, Karczewski D, Newman ET, Raskin KA, Lozano-Calderon SA. Debridement, Antibiotics, and Implant Retention (DAIR) Plus Offers Similar Periprosthetic Joint Infection Treatment Success Rates to Two-Stage Revision in Oncologic Megaprosthesis. J Arthroplasty 2024; 39:1820-1827. [PMID: 38224789 DOI: 10.1016/j.arth.2024.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/27/2023] [Accepted: 01/09/2024] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND Prosthetic joint infections (PJIs) after megaprosthesis implantation are associated with high rates of treatment failure and amputation. Our study analyzed PJI treatment success rates by surgical strategy and assessed risks of reinfection and amputation. METHODS We retrospectively analyzed the outcomes of patients diagnosed with PJI after undergoing megaprosthesis implantation for oncologic indications. The 2011 Musculoskeletal Infection Society criteria were used to define PJI. Reinfection, reoperation, and amputation for PJI recurrence were assessed. A total of 67 patients with megaprosthesis PJIs were included. There were fourteen patients who were treated with debridement, antibiotics, and implant retention (DAIR), 31 with DAIR plus (DAIR with modular component exchange and stem retention), and 21 with two-stage revisions. Kaplan-Meier estimates were used for survival analyses and Cox proportional hazards for risk factor analyses. RESULTS The two-year reinfection-free survival was 25% for DAIR and 60% for DAIR plus or two-stage revision (P = .049). The five-year amputation-free survival was 84% for DAIR plus or two-stage revision, and 48% for DAIR (P = .13). Reinfection-free, reoperation-free, and amputation-free survival were similar between DAIR plus and two-stage revision at the 2- and 5-year marks. Body mass index ≥30 (hazard ratio [HR] = 2.65) and chronic kidney disease (HR = 11.53) were risk factors for reinfection. Treatment with DAIR plus or two-stage revision (HR = 0.44) was a protective factor against reinfection. CONCLUSIONS A DAIR was associated with high rates of treatment failure and higher amputation rates than DAIR plus or 2-stage surgery. A DAIR plus was not inferior to 2-stage revision clearing a PJI and might be performed in patients who cannot withstand two-stage revision surgery.
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Affiliation(s)
- Marcos R Gonzalez
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
| | - José I Acosta
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts; School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico; Orthopedic and Arthritis Center for Outcomes Research, Brigham and Women's Hospital, Boston, Massachusetts
| | - Marilee J Clunk
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts; Department of Orthopaedic Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Angad D S Bedi
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
| | - Daniel Karczewski
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
| | - Erik T Newman
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
| | - Kevin A Raskin
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
| | - Santiago A Lozano-Calderon
- Musculoskeletal Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital Boston/Harvard Medical School, Boston, Massachusetts
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14
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Lübke J, Schmid A, Christen D, Oude Elberink HNG, Span LFR, Niedoszytko M, Gorska A, Lange M, Gleixner KV, Hadzijusufovic E, Stefan A, Angelova-Fischer I, Zanotti R, Bonifacio M, Bonadonna P, Shoumariyeh K, von Bubnoff N, Müller S, Perkins C, Elena C, Malcovati L, Hagglund H, Mattsson M, Parente R, Varkonyi J, Fortina AB, Caroppo F, Brockow K, Zink A, Breynaert C, Leven T, Yavuz AS, Doubek M, Sabato V, Schug T, Hartmann K, Triggiani M, Gotlib J, Hermine O, Arock M, Kluin-Nelemans HC, Panse J, Sperr WR, Valent P, Reiter A, Schwaab J. Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM. Blood Adv 2024; 8:2890-2900. [PMID: 38593217 PMCID: PMC11214361 DOI: 10.1182/bloodadvances.2024012756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 04/11/2024] Open
Abstract
ABSTRACT Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.
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Affiliation(s)
- Johannes Lübke
- Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
| | - Alicia Schmid
- Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
| | - Deborah Christen
- Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf, Aachen, Germany
| | - Hanneke N. G. Oude Elberink
- Department of Allergology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lambert F. R. Span
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marek Niedoszytko
- Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland
| | - Aleksandra Gorska
- Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland
| | - Magdalena Lange
- Department of Dermatology, Venereology and Allergology, Medical University of Gdańsk, Gdańsk, Poland
| | - Karoline V. Gleixner
- Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Emir Hadzijusufovic
- Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
- Department/University Clinic for Companion Animals and Horses, Internal Medicine Small Animals, University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria
| | - Alex Stefan
- University Clinic for Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria
| | - Irena Angelova-Fischer
- Department of Dermatology and Venereology, Allergy Center, Kepler University Hospital, Johannes Kepler University, Linz, Austria
| | - Roberta Zanotti
- Department of Medicine, Section of Hematology, Verona University Hospital, Verona, Italy
| | - Massimiliano Bonifacio
- Department of Medicine, Section of Hematology, Verona University Hospital, Verona, Italy
| | | | - Khalid Shoumariyeh
- Department of Medicine I, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nikolas von Bubnoff
- Department of Medicine I, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Sabine Müller
- Department of Dermatology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Cecelia Perkins
- Stanford Cancer Institute, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA
| | - Chiara Elena
- Hematology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luca Malcovati
- Hematology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Hans Hagglund
- Division of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Mattias Mattsson
- Division of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Roberta Parente
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Judit Varkonyi
- Department of Hematology, Semmelweis University, Budapest, Hungary
| | - Anna Belloni Fortina
- Department of Medicine, Pediatric Dermatology Unit, University of Padova, Padova, Italy
| | - Francesca Caroppo
- Department of Medicine, Pediatric Dermatology Unit, University of Padova, Padova, Italy
| | - Knut Brockow
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - Alexander Zink
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christine Breynaert
- KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group and MASTeL, University Hospitals Leuven, Leuven, Belgium
| | - Toon Leven
- KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group and MASTeL, University Hospitals Leuven, Leuven, Belgium
| | - Akif Selim Yavuz
- Division of Hematology, Istanbul Medical School, University of Istanbul, Istanbul, Turkey
| | - Michael Doubek
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno & Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Vito Sabato
- Department of Immunology-Allergology-Rheumatology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerpen, Belgium
| | - Tanja Schug
- Department of Dermatology and Venereology, University Hospital Graz, Graz, Austria
| | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland
- Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy
| | - Jason Gotlib
- Stanford Cancer Institute, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA
| | - Olivier Hermine
- French Reference Center for Mastocytosis, Hospital Necker, Assistance Publique Hôpitaux de Paris, Imagine Institute, University Paris Descartes, Paris, France
| | - Michel Arock
- French Reference Center for Mastocytosis, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, University Paris Sorbonne, Paris, France
| | - Hanneke C. Kluin-Nelemans
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jens Panse
- Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf, Aachen, Germany
| | - Wolfgang R. Sperr
- Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Peter Valent
- Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
| | - Juliana Schwaab
- Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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15
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Ni S, Zhong Z, Zhao Y, Chen F, Wu J, Yu H, Bai J. Sample size estimation for stratified cluster randomization trial with survival endpoint. Stat Methods Med Res 2024; 33:838-857. [PMID: 38549457 DOI: 10.1177/09622802241236953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
Cluster randomization trials with survival endpoint are predominantly used in drug development and clinical care research when drug treatments or interventions are delivered at a group level. Unlike conventional cluster randomization design, stratified cluster randomization design is generally considered more effective in reducing the impacts of imbalanced baseline prognostic factors and varying cluster sizes between groups when these stratification factors are adopted in the design. Failure to account for stratification and cluster size variability may lead to underpowered analysis and inaccurate sample size estimation. Apart from the sample size estimation in unstratified cluster randomization trials, there are no development of an explicit sample size formula for survival endpoint when a stratified cluster randomization design is employed. In this article, we present a closed-form sample size formula based on the stratified cluster log-rank statistics for stratified cluster randomization trials with survival endpoint. It provides an integrated solution for sample size estimation that account for cluster size variation, baseline hazard heterogeneity, and the estimated intracluster correlation coefficient based on the preliminary data. Simulation studies show that the proposed formula provides the appropriate sample size for achieving the desired statistical power under various parameter configurations. A real example of a stratified cluster randomization trial in the population with stable coronary heart disease is presented to illustrate our method.
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Affiliation(s)
- Senmiao Ni
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zihang Zhong
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yang Zhao
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feng Chen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingwei Wu
- Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, PA, USA
| | - Hao Yu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianling Bai
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
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Yongvanitchit K, Kum-Arb U, Limsalakpetch A, Im-Erbsin R, Ubalee R, Spring MD, Vesely BA, Waters N, Pichyangkul S. Superior protection in a relapsing Plasmodium cynomolgi rhesus macaque model by a chemoprophylaxis with sporozoite immunization regimen with atovaquone-proguanil followed by primaquine. Malar J 2024; 23:106. [PMID: 38632607 PMCID: PMC11022453 DOI: 10.1186/s12936-024-04933-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/04/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model. METHODS The animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 104 P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge. RESULTS Group 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow. CONCLUSIONS This research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax.
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Affiliation(s)
- Kosol Yongvanitchit
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Utaiwan Kum-Arb
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | | | - Rawiwan Im-Erbsin
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Ratawan Ubalee
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Michele D Spring
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Brian A Vesely
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Norman Waters
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand
| | - Sathit Pichyangkul
- Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
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Tembo D, Abobo FDN, Kaonga P, Jacobs C, Bessing B. Risk factors associated with neonatal mortality among neonates admitted to neonatal intensive care unit of the University Teaching Hospital in Lusaka. Sci Rep 2024; 14:5231. [PMID: 38433271 PMCID: PMC10909865 DOI: 10.1038/s41598-024-56020-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/29/2024] [Indexed: 03/05/2024] Open
Abstract
Globally, several children die shortly after birth and many more of them within the first 28 days of life. Sub-Sharan Africa accounts for almost half (43%) of the global neonatal death with slow progress in reduction. These neonatal deaths are associated with lack of quality care at or immediately after birth and in the first 28 days of life. This study aimed to determine the trends and risk factors of facility-based neonatal mortality in a major referral hospital in Lusaka, Zambia. We conducted retrospective analysis involving all neonates admitted in the University Teaching Hospital Neonatal Intensive Care Unit (UTH-NICU) in Lusaka from January 2018 to December 2019 (N = 2340). We determined the trends and assessed the factors associated with facility-based neonatal mortality using Generalized Linear Models (GLM) with a Poisson distribution and log link function. Overall, the facility-based neonatal mortality was 40.2% (95% CI 38.0-42.0) per 1000 live births for the 2-year period with a slight decline in mortality rate from 42.9% (95% CI 40.0-46.0) in 2018 to 37.3% (95% CI 35.0-40.0) in 2019. In a final multivariable model, home delivery (ARR: 1.70, 95% CI 1.46-1.96), preterm birth (ARR: 1.59, 95% CI 1.36-1.85), congenital anomalies (ARR: 1.59, 95% CI 1.34-1.88), low birthweight (ARR: 1.57, 95% CI 1.37-1.79), and health centre delivery (ARR: 1.48, 95% CI 1.25-1.75) were independently associated with increase in facility-based neonatal mortality. Conversely, hypothermia (ARR: 0.36, 95% CI 0.22-0.60), antenatal attendance (ARR: 0.76, 95% CI 0.68-0.85), and 1-day increase in neonatal age (ARR: 0.96, 95% CI 0.95-0.97) were independently associated with reduction in facility-based neonatal mortality. In this hospital-based study, neonatal mortality was high compared to the national and global targets. The improvement in neonatal survival observed in this study may be due to interventions including Kangaroo mother care already being implemented. Early identification and interventions to reduce the impact of risks factors of neonatal mortality in Zambia are important.
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Affiliation(s)
- Deborah Tembo
- School of Public Health, Department of Epidemiology and Biostatistics, University of Zambia, Lusaka, Zambia.
- Zambia National Public Health Institute, Lusaka, Zambia.
| | | | - Patrick Kaonga
- School of Public Health, Department of Epidemiology and Biostatistics, University of Zambia, Lusaka, Zambia
| | - Choolwe Jacobs
- School of Public Health, Department of Epidemiology and Biostatistics, University of Zambia, Lusaka, Zambia
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Kilpikoski S, Häkkinen AH, Repo JP, Kyrölä K, Multanen J, Kankaanpää M, Vainionpää A, Takala EP, Kautiainen H, Ylinen J. The McKenzie Method versus guideline-based advice in the treatment of sciatica: 24-month outcomes of a randomised clinical trial. Clin Rehabil 2024; 38:72-84. [PMID: 37605454 DOI: 10.1177/02692155231196393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
OBJECTIVE To compare the effectiveness of a McKenzie Method intervention in patients with sciatica with guideline-based patient education. DESIGN Multi-centre, assessor-blinded, parallel-group, randomised trial. SETTING Two tertiary hospitals providing operative spinal care. SUBJECTS Sciatica patients with magnetic resonance imaging-confirmed lumbar disc herniation compressing a nerve root. INTERVENTIONS The McKenzie group received specific back exercises for seven visits combined with an educational book, and the Control group received a single session of self-management guidance according to usual practices. MAIN MEASURES The primary outcome was the number of surgical operations. Secondary outcomes were pain measured using the Visual Analogue Scale, disability using the Oswestry Disability Index and health-related quality of life using a RAND-36 questionnaire at baseline and 24-month follow-up. RESULTS Altogether 66 patients, mean age of 43 years, of which 50% were females with long-lasting sciatica, mean 16 weeks, were randomised to two groups. Nineteen patients (29%) had surgery. There was no significant difference in surgery rates between the groups. Back and leg pain decreased, and disability improved in both groups. Health-related quality of life improved in six dimensions out of eight in both groups. There were no significant between-group changes in the patient-reported outcomes at the follow-up. CONCLUSIONS Multiple sessions of McKenzie-based back exercises with a McKenzie-specific patient's educational book produced effects equal to guideline-based advice at long-term follow-up. However, the power of these results is diminished due to the small patient population and confounding factors.
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Affiliation(s)
- Sinikka Kilpikoski
- Department of Physical Medicine and Rehabilitation, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Arja H Häkkinen
- Department of Physical Medicine and Rehabilitation, Jyväskylä Central Hospital, Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Jussi P Repo
- Department of Orthopaedics and Traumatology, Tampere University Hospital, Tampere, Finland
| | - Kati Kyrölä
- Orthopaedics and Traumatology, Hospital NOVA, Central Finland Health Care District, Jyväskylä, Finland
| | - Juhani Multanen
- Department of Physical Medicine and Rehabilitation, Jyväskylä Central Hospital, Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Markku Kankaanpää
- Department of Rehabilitation and Psychosocial Support, Tampere University Hospital, Tampere, Finland
| | - Aki Vainionpää
- Department of Rehabilitation, Seinäjoki Central Hospital, Seinäjoki, Finland
| | - Esa-Pekka Takala
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Hannu Kautiainen
- Primary Health Care Unit, Kuopio University Hospital, Kuopio, Finland
- Folkhälsan Research Center, Helsinki, Finland
| | - Jari Ylinen
- Department of Physical Medicine and Rehabilitation, Jyväskylä Central Hospital, Jyväskylä, Finland
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Chen Y, Lam KF, Xu J. Sample size calculation for multi-arm parallel design with restricted mean survival time. Stat Methods Med Res 2024; 33:130-147. [PMID: 38093411 DOI: 10.1177/09622802231219852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2024]
Abstract
With the recent advances in oncology treatment, restricted mean survival time (RMST) is increasingly being used to replace the routine approach based on hazard ratios in randomized controlled trials for time-to-event outcomes. While RMST has been widely applied in single-arm and two-arm designs, challenges still exist in comparing RMST in multi-arm trials with three or more groups. In particular, it is unclear in the literature how to compare more than one intervention simultaneously or perform multiple testing based on RMST, and sample size determination is a major obstacle to its penetration to practice. In this paper, we propose a novel method of designing multi-arm clinical trials with right-censored survival endpoint based on RMST that can be applied in both phase II/III settings using a global χ 2 test as well as a modeling-based multiple comparison procedure. The framework provides a closed-form sample size formula built upon a multi-arm global test and a sample size determination procedure based on multiple-comparison in the phase II dose-finding study. The proposed method enjoys strong robustness and flexibility as it requires less a priori set-up than conventional work, and obtains a smaller sample size while achieving the target power. In the assessment of sample size, we also incorporate practical considerations, including the presence of non-proportional hazards and staggered patient entry. We evaluate the validity of our method through simulation studies under various scenarios. Finally, we demonstrate the accuracy and stability of our method by implementing it in the design of two real clinical trial examples.
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Affiliation(s)
- Yaxian Chen
- Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong
| | - Kwok Fai Lam
- Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong
- Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Jiajun Xu
- Janssen Research & Development, China
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20
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Li B, Zhang J, Yang W, Su L, Yan F. Group sequential design with maximin efficiency robust test for immunotherapy with generalized delayed treatment effect. Pharm Stat 2024; 23:107-133. [PMID: 37859531 DOI: 10.1002/pst.2341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 07/24/2023] [Accepted: 09/27/2023] [Indexed: 10/21/2023]
Abstract
The delayed treatment effect is a common feature of immunotherapy, characterized by a gradual onset of action ranging from no effect to full effect. In this study, we propose a generalized delayed treatment effect function to depict the delayed effective process precisely and flexibly. To reduce potential power loss caused by the delayed treatment effect in a group sequential trial, we employ the maximin efficiency robust test, which enhances power robustness across a range of possible delays. We present novel approaches based on the Markov chain method for determining group sequential boundaries, calculating the power function, and estimating the maximum sample size through iterative regressions between the square root of the maximum sample size and the normal quantile of power. Extensive simulation studies validate the effectiveness of our approaches, particularly in balanced trials, demonstrating the validity of group sequential boundaries and the accuracy of maximum sample size estimations. Additionally, we utilize a real trial as an example to compare our considered trial with group sequential trials using the log-rank and generalized piecewise weighted log-rank tests. The results show significantly reduced maximum sample sizes, highlighting the economic advantage of our approach.
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Affiliation(s)
- Bosheng Li
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jingyi Zhang
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenyun Yang
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liwen Su
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Fangrong Yan
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
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21
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Kilpikoski S, Suominen EN, Repo JP, Häkkinen AH, Kyrölä K, Kautiainen H, Ylinen J. Comparison of magnetic resonance imaging findings among sciatica patients classified as centralizers or non-centralizers. J Man Manip Ther 2023; 31:358-367. [PMID: 36756675 PMCID: PMC10566442 DOI: 10.1080/10669817.2023.2174555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 01/22/2023] [Indexed: 02/10/2023] Open
Abstract
OBJECTIVE To compare if the degenerative findings from MRI differ between the sciatica patients classified as centralizers (CEN) and non-centralizers (Non-CEN) according to the McKenzie Method of mechanical diagnosis and therapy. STUDY DESIGN A cross-sectional study. METHODS Patients (N = 100) referred to a spine clinic of a single tertiary hospital for specialist consultation for sciatica. The McKenzie-based assessment was performed by the mechanical diagnosis and therapy-trained physiotherapists. Clinical data and prevalence of lumbar MRI findings were compared between the groups. RESULTS There was no significant difference in leg pain intensity between the groups. The Non-CEN had significantly more intense back pain, mean 56 (SD 30) and were more disabled 44 (SD 15) compared to the CEN mean 41 (SD 25) and mean 31 (11), measured with a visual analogue scale (0-100), and the Oswestry Disability Index (0-100), respectively. The CEN had more severe degenerative findings on MRI than the Non-CEN: vertebral end-plate changes were 63% and 43%; mean Pfirrmann's disc degeneration lumbar summary score was 12.8, and 10.6; and severity score of total damage was 12.0 and 10.1, respectively. There were differences neither in disc contour changes nor nerve root stenosis on MRI. CONCLUSIONS Sciatica patients classified as non-centralizers had significantly more severe back pain, and were significantly more disabled than centralizers, who instead had more severe degenerative findings on MRI. Thus, classification to non-centralizers by the McKenzie method seems not predict higher incidence of degenerative findings on MRI compared to centralizers.
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Affiliation(s)
- Sinikka Kilpikoski
- Department of Physical and Rehabilitation Medicine, Centra’ Finland Health Care District Hospital, Jyvaskyla, Finland
| | | | - Jussi P Repo
- Department of Orthopaedics and Traumatology, Tampere University Hospital, Tampere, Finland
| | - Arja H Häkkinen
- Faculty of Health Sciences, Univeristy of Jyväskylä, Jyväskylä, Finland
| | - Kati Kyrölä
- Consultant Surgeon Orthopaedics and Traumatology, Docent. Chief Orthopaedic Surgeon, Hospital NOVA, Central Finland Health Care District, Jyvaskyla, Finland
| | - Hannu Kautiainen
- Primary Health Care Unit, Kuopio University Hospital, Helsinki, Finland
| | - Jari Ylinen
- Department of Physical and Rehabilitation Medicine, Centra’ Finland Health Care District Hospital, Jyvaskyla, Finland
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22
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Lee Y, Shin JH, Seo SM, Choi IJ, Lee JY, Lee JW, Park MW, Kang TS, Choi WG, Jeon KH, Lim HS, Joo HJ, Rhee SJ, Seo JB, Park MS, Park SH, Lim YH. Influence of early dose reduction of ticagrelor on clinical outcomes following percutaneous coronary intervention for complex lesions. Sci Rep 2023; 13:15481. [PMID: 37726368 PMCID: PMC10509174 DOI: 10.1038/s41598-023-42655-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Ticagrelor-based dual antiplatelet therapy (DAPT) provides potent antiplatelet inhibition but may increase the bleeding risk in Asian populations. We investigated the influence of early ticagrelor dose reduction (120 mg) on clinical outcomes in Korean patients undergoing percutaneous coronary intervention (PCI). A multicenter prospective clinical cohort study was conducted with patients who received standard-dose ticagrelor-based DAPT (180 mg) after PCI for complex lesions. Major adverse cardiovascular event (MACE: a composite of cardiovascular death, myocardial infarction, stroke, and repeat revascularization), bleeding, and net adverse clinical events (NACE: a composite of MACE and bleeding) were assessed. Among the 772 patients on standard-dose ticagrelor-based DAPT, 115 (14.8%) switched to low-dose ticagrelor-based DAPT (120 mg) within 6 months. Common reasons for the regimen changes were switching as planned (38.8%), dyspnea (25.5%), and bleeding (23.6%). A multivariable Cox proportional hazard model (CPH) showed that the risks of MACE, bleeding, and NACE were not different between the low-dose and standard-dose groups throughout the entire follow-up period and the period beyond 6 months post-PCI. Time-varying multivariable CPH models of the ticagrelor dose reduction yielded similar results. A reduction of the ticagrelor dose within 6 months after PCI is feasible and safe even in patients with complex lesions harboring a high ischemic event risk.
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Affiliation(s)
- Yonggu Lee
- Division of Cardiology, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Jeong-Hun Shin
- Division of Cardiology, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Suk Min Seo
- Division of Cardiology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ik Jun Choi
- Division of Cardiology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Jong-Young Lee
- Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jun-Won Lee
- Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Mahn-Won Park
- Division of Cardiology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Tae Soo Kang
- Division of Cardiology, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - Woong Gil Choi
- Department of Internal Medicine, College of Medicine, Chungbuk National University Hospital, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Ki-Hyun Jeon
- Division of Cardiology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hong-Seok Lim
- Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Hyung Joon Joo
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Sang Jae Rhee
- Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Republic of Korea
| | - Jae-Bin Seo
- Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Myung Soo Park
- Division of Cardiology, Dongtan Sacred Heart Hospital, 7, Keunjaebong-gil, Hwaseong-si, Gyeonggi-do, 18450, Republic of Korea
| | - Sang-Ho Park
- Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, 31, Suncheonhyang 6-gil, Dongnam-gu, Cheonan, 31151, Republic of Korea.
| | - Young-Hyo Lim
- Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Sungdong-gu, Seoul, 04763, Republic of Korea.
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García-Padilla P, Dávila-Rúales V, Hurtado DC, Vargas DC, Muñoz OM, Jurado MA. A Comparative Study on Graft and Overall Survival Rates Between Diabetic and Nondiabetic Kidney Transplant Patients Through Survival Analysis. Can J Kidney Health Dis 2023; 10:20543581231199011. [PMID: 37719299 PMCID: PMC10503289 DOI: 10.1177/20543581231199011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 07/09/2023] [Indexed: 09/19/2023] Open
Abstract
Background Patients with diabetes mellitus (DM) have worse graft and overall survival, but recent evidence suggests that the difference is no longer significant. Objective To compare the outcomes between patients with end-stage kidney disease due to DM (ESKD-DM) and ESKD due to nondiabetic etiology (ESKD-non-DM) who underwent kidney transplantation (KT) up to 10 years of follow-up. Design Survival analysis of a retrospective cohort. Setting and Patients All patients who underwent KT at the Hospital Universitario San Ignacio, Colombia, between 2004 and 2022. Measurements Overall and graft survival in ESKD-DM and ESKD-non-DM who received KT. Patients who died with functional graft were censored for the calculation of kidney graft survival. Methods Log-rank test, Cox proportional hazards model, and competing risk analysis were used to compare overall and graft survival in patients with ESKD-DM and ESKD-non-DM who underwent KT. Results A total of 375 patients were included: 60 (16%) with ESKD-DM and 315 (84%) with ESKD-non-DM. Median follow-up was 83.3 months. Overall survival was lower in patients with ESKD-DM at 5 (75.0% vs 90.8%, P < .001) and 10 years (55.0% vs 86.7%, P < .001). Cardiovascular death was higher in patients with diabetes (27.3% vs 8.2%, P = .021). Death-censored graft survival was similar in both groups (96.7% vs 93.3% at 5 years, P = .324). On multivariate analysis, the factors associated with global survival were DM (hazard ratio [HR] = 2.11, 95% confidence interval [CI] = 1.23-3.60, P = .006), recipient age (HR = 1.05, 95% CI = 1.02-1.08, P < .001), delayed graft function (HR = 2.07, 95% CI = 1.24-3.46, P = .005), and donor age (HR = 1.03, 95% CI = 1.01-1.05, P = .002). In the competing risk analysis, DM was associated with mortality only in the cardiovascular death group (sub-hazard ratio [SHR] = 6.06, 95% CI = 1.01-36.4, P = .049). Limitations Change in diabetes treatment received over time and adherence to glycemic targets were not considered. The sample size is relatively small, which limits the precision of our estimates. The Kidney Donor Profile Index and the occurrence of treated acute rejection were not included in the regression models. Conclusion Overall survival is lower in patients with diabetes, possibly due to older age and cardiovascular comorbidities. Therefore, patients with diabetes should be followed more closely to control cardiovascular risk factors. However, there is no difference in graft survival.
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Affiliation(s)
- Paola García-Padilla
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
- Unit of Nephrology, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Valentina Dávila-Rúales
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Diana C. Hurtado
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
- Unit of Nephrology, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Diana C. Vargas
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
- Unit of Nephrology, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Oscar M. Muñoz
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Mayra A. Jurado
- Department of Internal Medicine, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia
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Ley H, Skorniewska Z, Harrison PJ, Taquet M. Risks of neurological and psychiatric sequelae 2 years after hospitalisation or intensive care admission with COVID-19 compared to admissions for other causes. Brain Behav Immun 2023; 112:85-95. [PMID: 37263366 PMCID: PMC10228171 DOI: 10.1016/j.bbi.2023.05.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/05/2023] [Accepted: 05/25/2023] [Indexed: 06/03/2023] Open
Abstract
The association between COVID-19 and subsequent neurological and psychiatric disorders is well established. However, two important questions remain unanswered. First, what are the risks in those admitted to intensive care unit (ICU) with COVID-19? Admission to ICU is itself associated with neurological and psychiatric sequelae and it is not clear whether COVID-19 further increases those risks or changes their profile. Second, what are the trajectories of neurological and psychiatric risks in patients admitted to hospital or ICU with COVID-19, and when do the risks subside? We sought to answer these two questions using a retrospective cohort study based on electronic health records (EHR) data from the TriNetX Analytics Network (covering 89 million patients, mostly in the USA). Cohorts of patients admitted to hospital or ICU with COVID-19 were propensity score-matched (for 82 covariates capturing risk factors for COVID-19 and more severe COVID-19 illness) to patients admitted to hospital or ICU (respectively) for any other reason. Matched cohorts were followed for up to two years and the risk of 14 neurological and psychiatric outcomes were compared. A total of 280,173 patients admitted to hospital and 46,573 patients admitted to ICU with COVID-19 were successfully matched to an equal number of patients admitted to hospital or ICU for any other reason. Those hospitalised with COVID-19 were found to be at a greater risk of a range of neurological and psychiatric outcomes including seizure/epilepsy, encephalitis, myoneural junction/muscle disease, Guillain-Barré syndrome (GBS), dementia, cognitive deficits, psychotic disorder, mood and anxiety disorders, but not ischaemic stroke or intracranial haemorrhage. When risks were elevated after COVID-19, most remained so for the whole two years of follow-up (except for mood and anxiety disorders). Risk profiles and trajectories were substantially different among those admitted to ICU: compared to those admitted for any other reasons, those admitted with COVID-19 were at a greater risk of myoneural junction/muscle disease, GBS, cognitive deficits and anxiety disorder, but at a significantly lower risk of ischaemic stroke, intracranial haemorrhage, encephalitis, and mood disorder. When elevated, the risks in those admitted to ICU with COVID-19 were mostly short-lived. In summary, risks of neurological and psychiatric sequelae in patients hospitalised with COVID-19 are wide ranging and long standing whereas those in patients admitted to ICU with COVID-19 are similar to, or lower than, the risks observed post-ICU admission for any other cause. These contrasting risk trajectories are relevant for researchers, clinicians, patients, and policymakers.
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Affiliation(s)
- Harriet Ley
- Medical Sciences Division, University of Oxford, Oxford, UK
| | | | - Paul J Harrison
- Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK
| | - Maxime Taquet
- Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.
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Campbell M, Kiss C, Zimmermann M, Riccheri C, Kowalczyk J, Felice MS, Kuzmanovic M, Kovacs G, Kosmidis H, Gonzalez A, Bilic E, Castillo L, Kolenova A, Jazbec J, Popa A, Konstantinov D, Kappelmayer J, Szczepanski T, Dworzak M, Buldini B, Gaipa G, Marinov N, Rossi J, Nagy A, Gaspar I, Stary J, Schrappe M. Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial. J Clin Oncol 2023:JCO2201760. [PMID: 37141547 DOI: 10.1200/jco.22.01760] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023] Open
Abstract
PURPOSE The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated. PATIENTS AND METHODS We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR. RESULTS The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84). CONCLUSION The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.
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Affiliation(s)
- Myriam Campbell
- Department of Pediatric Hematology and Oncology, Hospital Roberto del Rio, Universidad de Chile, Chilean National Pediatric Oncology Group, PINDA, Santiago, Chile
| | - Csongor Kiss
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Martin Zimmermann
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Cecilia Riccheri
- Argentine Group for the Treatment of Acute Leukemia, GATLA, Buenos Aires, Argentina
| | - Jerzy Kowalczyk
- Department of Pediatric, Hematology, Oncology, and Transplantology, Medical University of Lublin, Lublin, Poland
| | - Maria S Felice
- Hematology and Oncology Department, Hospital de Pediatría Prof. Dr Juan P. Garrahan, SAHOP, Buenos Aires, Argentina
| | - Milos Kuzmanovic
- Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Faculty of Medicine, Belgrade, Serbia
| | - Gabor Kovacs
- 2nd Department of Pediatrics Semmelweis University, Budapest, Hungary
| | - Helen Kosmidis
- Pediatric and Adolescent Oncology Clinic, Children's Hospital MITERA, Athens, Greece
| | | | - Ernest Bilic
- School of Medicine Division of Pediatric Hematology and Oncology, University Hospital Center, University of Zagreb, Zagreb, Croatia
| | - Luis Castillo
- Pediatric Hemato-Oncology Department, Hospital Pereira Rossell, Pérez Scremini Foundation, Montevideo, Uruguay
| | - Alexandra Kolenova
- Department of Pediatric Hematology and Oncology, National Institute of Children's Diseases and Medical School, Comenius University, Bratislava, Slovakia
| | - Janez Jazbec
- University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Alexander Popa
- Pediatric Oncology and Hematology Research Institute of N.N.Blokhin National Cancer Research Center, Center, Moscow, Russia
| | - Dobrin Konstantinov
- Pediatric Hematology & Oncology Department, University Hospital "Tsaritsa Johanna-ISUL", Sofia, Bulgaria
| | - Janos Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tomasz Szczepanski
- Department of Pediatric Hematology and Oncology, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Michael Dworzak
- St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
| | - Barbara Buldini
- Mother and Child's Health Department, Division of Pediatric Hematology, Oncology and Stem Cell Transplant, University of Padova, Padova, Veneto, Italy
| | - Giuseppe Gaipa
- Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Neda Marinov
- Chilean National Pediatric Oncology Group, PINDA, Hospital Roberto del Rio/Universidad de Chile, Santiago, Chile
- Hospital del Salvador, Universidad de Chile, Santiago, Chile
| | - Jorge Rossi
- Immunology and Rheumatology Department, Hospital de Pediatría Prof. Dr Juan P. Garrahan, Buenos Aires, Argentina
| | - Attila Nagy
- Department of Interventional Epidemiology, Faculty of Public Health, University of Debrecen, Debrecen, Hungary
| | - Imre Gaspar
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Jan Stary
- Department of Pediatric Hematology and Oncology Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Martin Schrappe
- Department of Pediatric and Adolescent Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
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Geremew H, Wolde A, Kassa GM. Incidence and predictors of loss to follow-up among women on option B+ PMTCT program in northwest Ethiopia. A retrospective follow-up study. PLoS One 2023; 18:e0280546. [PMID: 36649312 PMCID: PMC9844877 DOI: 10.1371/journal.pone.0280546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Loss to follow-up from lifelong antiretroviral therapy continued to be a major challenge affecting virtual elimination of mother-to-child transmission of human immunodeficiency virus, especially in Sub-Saharan Africa. Although there was a study conducted in Ethiopia, loss to follow-up was not clearly defined and some important variables were not addressed. Thus, this study was conducted to determine the incidence of loss to follow-up and its predictors among women on option B+ lifelong antiretroviral therapy program in Pawi district health facilities, northwest Ethiopia. METHODS An institutional-based retrospective follow-up study was conducted among 365 women who were enrolled for option B+ prevention of mother-to-child transmission service between June 2013 and March 2021 in Pawi district health facilities. A standard pretested checklist was used to extract data from all eligible women's records. The Kaplan-Meier survival curve for estimating survival probability and Cox proportional hazards model to identify independent predictors of loss to follow-up were employed after checking for proportional hazards assumptions using STATA-14 statistical software. RESULT The overall incidence of loss to follow-up was 12.04 (95% CI: 9.50, 15.20) per 1000 person-months of observation time. Residing outside the catchment area (adjusted hazard ratio (AHR): 3.08, 95% CI: 1.59, 5.98), lactating at enrollment (AHR: 2.43, 95% CI: 1.24, 4.77), living in a sero-discordant relationship (AHR: 2.5, 95% CI: 1.13, 5.53), lack of sero-status disclosure (AHR: 2.59, 95% CI: 1.15, 5.85), new enrollment to lifelong antiretroviral therapy (AHR: 2.07, 95% CI: 1.05, 4.11), and fair (AHR: 2.69, 95% CI: 1.2, 6.04) or poor (AHR: 5.78, 95% CI: 2.76, 12.12) antiretroviral drug adherence level were independent predictors of loss to follow-up. CONCLUSION We found a higher incidence of loss to follow-up relative to previous studies in Ethiopia. Thus, strengthening adherence support interventions, and effective counseling on sero-status disclosure and male partner involvement are important to retain women in care.
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Affiliation(s)
- Habtamu Geremew
- College of Health Science, Oda Bultum University, Chiro, Ethiopia
| | - Awraris Wolde
- Department of Public Health, College of Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Getachew Mullu Kassa
- Department of Public Health, College of Health Science, Debre Markos University, Debre Markos, Ethiopia
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Chen X, Wu H, Li L, Zhao X, Zhang C, Wang WE. The prognostic utility of GRACE risk score in predictive adverse cardiovascular outcomes in patients with NSTEMI and multivessel disease. BMC Cardiovasc Disord 2022; 22:568. [PMID: 36572851 PMCID: PMC9791745 DOI: 10.1186/s12872-022-03025-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/21/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND GRACE risk score models are capable of predicting all-cause mortality of non-ST elevation myocardial infarction (NSTEMI) patients. However, its utility for evaluating major adverse cardiovascular events (MACE) in NSTEMI patients with multivessel disease (MVD) remains unclear. METHODS AND RESULTS This study was designed as a retrospective cohort study that recruited patients with NSTEMI and multivessel disease between September 2013 and December 2018 in Daping Hospital, Chongqing, China. The primary outcome was a composite outcome that included all-cause mortality, recurrent angina, non-fatal myocardial infarction, coronary re-vascularization, and non-fatal strokes. Of the 827 patients with NSTEMI, 32 did not complete follow-up and 430 were excluded because of single-vessel disease. The remaining 365 NSTEMI patients with MVD had a median follow-up of 3.0 (IQR 2.6-3.3) years, 78 patients experienced outcomes. The GRACE risk score predicted the MACE (hazard ratio 1.014, 95% CI 1.006-1.021, P < 0.001). The GRACE risk score performed well in predicting all-cause mortality (c-statistic 0.72, 95% CI 0.59-0.85, P = 0.001) in MVD but was less powerful in predicting MACE (c-statistic 0.69, 95% CI 0.62-0.75, P < 0.001). When combining the GRACE risk score with the SYNTAX score, and blood urea nitrogen for predicting all-cause mortality and MACE events, the c-statistic value increased to 0.82 and 0.81 (P < 0.001). CONCLUSION In NSTEMI patients with MVD, the GRACE score showed an acceptable predictive value for all-cause mortality, but it was less powerful in predicting MACE. Blood urea nitrogen may be valuable in assessing long-term cardiovascular events in patients with MVD.
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Affiliation(s)
- Xiaokang Chen
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China ,Department of Cardiology, Santai County People’s Hospital (Affiliated Hospital of North Sichuan Medical College in Santai County), Mianyang, 621100 China
| | - Hao Wu
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China
| | - Liangpeng Li
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China
| | - Xiaofang Zhao
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China
| | - Chao Zhang
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China
| | - Wei Eric Wang
- grid.410570.70000 0004 1760 6682Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), 10 Changjiang Branch Road, Chongqing, 400042 China
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28
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Li J, Jung SH. Group sequential testing for cluster randomized trials with time-to-event endpoint. Biometrics 2022; 78:1353-1364. [PMID: 34076257 DOI: 10.1111/biom.13498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 04/27/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022]
Abstract
We propose group sequential methods for cluster randomized trials (CRTs) with time-to-event endpoint. The alpha spending function approach is used for sequential data monitoring. The key to this approach is determining the joint distribution of test statistics and the information fraction at the time of interim analysis. We prove that the sequentially computed log-rank statistics in CRTs do not have independent increment property. We also propose an information fraction for group sequential trials with clustered survival data and a corresponding sample size determination approach. Extensive simulation studies are conducted to evaluate the performance of our proposed testing procedure using some existing alpha spending functions in terms of expected sample size and maximal sample size. Real study examples are taken to demonstrate our method.
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Affiliation(s)
- Jianghao Li
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Sin-Ho Jung
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
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29
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Kou Y, Zhao Q, Yuan D, Ren X. Evaluation of GLDA-acid on sludge treatment effect and seed germination analysis. JOURNAL OF ENVIRONMENTAL MANAGEMENT 2022; 320:115958. [PMID: 36056503 DOI: 10.1016/j.jenvman.2022.115958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/29/2022] [Accepted: 08/03/2022] [Indexed: 06/15/2023]
Abstract
Mixtures of N, N-bis(carboxymethyl)-L-glutamic acid tetrasodium salt (GLDA) with citric acid (CA), glutamic acid (GLU), and aspartic acid (ASP) at the optimal proportion of 1:1, 1:2, and 2:1, respectively. They were employed for heavy metal removal from the sludge. The removal rate of common heavy metals (Cu, Pb, Zn, Ni, Cr, and Cd) and the retention degree of nutrients (total nitrogen, total phosphorus, available-N, Olsen-P, and organic matter) in the treated sludge were analyzed. Fuzzy comprehensive evaluation of the sludge was performed using MATLAB to determine the agricultural grade of the sludge. The sludge after GLDA-acid treatment was mixed with soil at different proportions, and Chinese cabbage, cucumber, and wheat were cultured. SPSS was used for survival analysis to analyze the feasibility of the sludge agriculture. The results showed that the optimal ratio of GLDA-CA and GLDA-GLU was 1:2 and that of GLDA-ASP was 1:1. After GLDA-acid treatment, the sludge was classified as Grade A agricultural sludge based on MATLAB fuzzy comprehensive evaluation and analysis. When the amount of sludge added was 20%, the growth of Chinese cabbage, cucumber, and wheat was promoted. Survival analysis further proved that the amount of sludge only affected the median germination time. Without considering the economic benefits, GLDA-acid can be preferred for sludge treatment, which can not only effectively remove heavy metals in sludge, but also have a small impact on agricultural use.
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Affiliation(s)
- Yingying Kou
- Key Laboratory of Urban Stormwater System and Water Environment, Ministry of Education, Beijing University of Civil Engineering and Architecture, Beijing, 100044, China.
| | - Qian Zhao
- NO.1 Design and Research Institute, Qingdao Tengyuan Design Institute CO.,LTD., Qingdao, 266101, China
| | - Donghai Yuan
- Key Laboratory of Urban Stormwater System and Water Environment, Ministry of Education, Beijing University of Civil Engineering and Architecture, Beijing, 100044, China
| | - Xianghao Ren
- Key Laboratory of Urban Stormwater System and Water Environment, Ministry of Education, Beijing University of Civil Engineering and Architecture, Beijing, 100044, China
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30
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Thomas KS, Dosa DM, Fisher A, Gadbois E, Harrison J, Hilgeman M, Largent EA, Lima J, McAuliff K, McCreedy E, Mills W, Ornstein KA, Shield RR, Barron M, Callaghan S, Clark K, Culak C, Faris V, Frankhauser AE, Huerta S, Krause K, Martinez I, Mayer A, Rodriguez J, Theilheimer L, Truelove W, Wilson I, Gutman R. Home-delivered meals for people with dementia: Which model delays nursing home placement? - Protocol for a feasibility pilot. Contemp Clin Trials 2022; 121:106897. [PMID: 36055581 PMCID: PMC9817376 DOI: 10.1016/j.cct.2022.106897] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/29/2022] [Accepted: 08/22/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Home-delivered meals promote food security, socialization, and independence among homebound older adults. However, it is unclear which of the two predominant modes of meal delivery, daily-delivered vs. drop-shipped, frozen meals, promotes community living for homebound older adults with dementia. Our objective is to present the protocol for a pilot multisite, two-arm, pragmatic feasibility trial comparing the effect of two modes of meal delivery on nursing home placement among people with dementia. We include justifications for individual randomization with different consent processes and waivers for specific elements of the trial. METHODS 236 individuals with dementia on waiting lists at three Meals on Wheels programs' in Florida and Texas will be randomized to receive either: 1) meals delivered multiple times per week by a Meals on Wheels volunteer or paid driver who may socialize with and provide an informal wellness check or 2) frozen meals that are mailed to participants' homes every two weeks. We will evaluate and refine processes for recruitment and randomization; assess adherence to the intervention; identify common themes in participant experience; and test processes for linking participant data with Medicare records and nursing home assessment data. We will conduct exploratory analyses examining time to nursing home placement, the primary outcome for the larger trial. CONCLUSION This pilot will inform the follow-on large-scale, definitive pragmatic trial. In addition, the justifications for individual randomization with differing consent procedures for elements of a pragmatic trial provide a model for future trialists looking to develop ethical and feasible pragmatic studies enrolling people with dementia.
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Affiliation(s)
- Kali S. Thomas
- Brown University School of Public Health, Providence, RI, USA,Providence VA Medical Center, Providence, RI, USA,Corresponding author at: Brown University School of Public Health, 21 S. Main Street, Providence, RI, 02912, USA. (K.S. Thomas)
| | - David M. Dosa
- Providence VA Medical Center, Providence, RI, USA,Brown University, Providence, RI, USA
| | - Alison Fisher
- Brown University School of Public Health, Providence, RI, USA
| | - Emily Gadbois
- Brown University School of Public Health, Providence, RI, USA
| | - Jill Harrison
- Brown University School of Public Health, Providence, RI, USA
| | - Michelle Hilgeman
- Research & Development Service, Tuscaloosa VA Medical Center, Tuscaloosa, AL, USA,Psychology Department, & Alabama Research Institute on Aging, The University of Alabama, Tuscaloosa, AL, USA,Department of Medicine, Division of Gerontology, Geriatrics, & Palliative Care, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Emily A. Largent
- Perelman School of Medicine, University of Pennsylvania, Phildelphia, PA, USA
| | - Julie Lima
- Brown University School of Public Health, Providence, RI, USA
| | - Katie McAuliff
- Brown University School of Public Health, Providence, RI, USA
| | - Ellen McCreedy
- Brown University School of Public Health, Providence, RI, USA
| | - Whitney Mills
- Brown University School of Public Health, Providence, RI, USA,Providence VA Medical Center, Providence, RI, USA
| | | | - Renee R. Shield
- Brown University School of Public Health, Providence, RI, USA
| | | | | | - Kayla Clark
- Visiting Nurse Association of Texas, Dallas, TX, USA
| | - Chris Culak
- Visiting Nurse Association of Texas, Dallas, TX, USA
| | | | | | | | | | | | | | | | | | | | - Inga Wilson
- Visiting Nurse Association of Texas, Dallas, TX, USA
| | - Roee Gutman
- Brown University School of Public Health, Providence, RI, USA
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Hong W, McLachlan SA, Moore M, Mahar RK. Improving clinical trials using Bayesian adaptive designs: a breast cancer example. BMC Med Res Methodol 2022; 22:133. [PMID: 35508968 PMCID: PMC9066830 DOI: 10.1186/s12874-022-01603-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To perform virtual re-executions of a breast cancer clinical trial with a time-to-event outcome to demonstrate what would have happened if the trial had used various Bayesian adaptive designs instead. METHODS We aimed to retrospectively "re-execute" a randomised controlled trial that compared two chemotherapy regimens for women with metastatic breast cancer (ANZ 9311) using Bayesian adaptive designs. We used computer simulations to estimate the power and sample sizes of a large number of different candidate designs and shortlisted designs with the either highest power or the lowest average sample size. Using the real-world data, we explored what would have happened had ANZ 9311 been conducted using these shortlisted designs. RESULTS We shortlisted ten adaptive designs that had higher power, lower average sample size, and a lower false positive rate, compared to the original trial design. Adaptive designs that prioritised small sample size reduced the average sample size by up to 37% when there was no clinical effect and by up to 17% at the target clinical effect. Adaptive designs that prioritised high power increased power by up to 5.9 percentage points without a corresponding increase in type I error. The performance of the adaptive designs when applied to the real-world ANZ 9311 data was consistent with the simulations. CONCLUSION The shortlisted Bayesian adaptive designs improved power or lowered the average sample size substantially. When designing new oncology trials, researchers should consider whether a Bayesian adaptive design may be beneficial.
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Affiliation(s)
- Wei Hong
- Department of Medical Oncology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia.
| | - Sue-Anne McLachlan
- Department of Medical Oncology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Parkville, VIC, Australia
| | - Melissa Moore
- Department of Medical Oncology, St Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia
| | - Robert K Mahar
- Biostatistics Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population Health, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Parkville, VIC, Australia
- Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, VIC, Australia
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Rist PM, Sesso HD, Johnson LG, Aragaki AK, Wang L, Rautiainen S, Hazra A, Tobias DK, LeBoff MS, Schroeter H, Friedenberg G, Copeland T, Clar A, Tinker LF, Hunt RP, Bassuk SS, Sarkissian A, Smith DC, Pereira E, Carrick WR, Wion ES, Schoenberg J, Anderson GL, Manson JE. Design and baseline characteristics of participants in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Contemp Clin Trials 2022; 116:106728. [PMID: 35288332 PMCID: PMC9133193 DOI: 10.1016/j.cct.2022.106728] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 11/15/2022]
Abstract
Background Cocoa extract and multivitamins have been proposed to reduce the risk of cardiovascular disease (CVD) and cancer, respectively. However, few randomized clinical trials have tested their long-term effects on these outcomes. Methods The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of a cocoa extract supplement and a multivitamin supplement to reduce the risk of CVD and cancer. Here we describe the pragmatic, hybrid design of the trial and baseline characteristics of the trial participants. Results The nationwide study population includes 21,442 U.S. women aged ≥65 years and men aged ≥60 years without baseline myocardial infarction (MI), stroke, or a recent (within the past 2 years) cancer diagnosis. Participants were randomized in a 2 × 2 factorial design to one of four groups: (1) cocoa extract (containing 500 mg/d flavanols, including 80 mg (-)-epicatechin) and a multivitamin (Centrum Silver©); (2) cocoa extract and multivitamin placebo; (3) multivitamin and cocoa extract placebo; or (4) both placebos. Randomization successfully distributed baseline demographic, clinical, behavioral, and dietary characteristics across treatment groups. Baseline biospecimens were collected from 6867 participants, with at least one follow-up biospecimen from 2142 participants. The primary outcome for the cocoa extract intervention is total CVD (a composite of MI, stroke, cardiovascular mortality, coronary revascularization, unstable angina requiring hospitalization, carotid artery surgery, and peripheral artery surgery); the primary outcome for the multivitamin intervention is total invasive cancer. Conclusion COSMOS will provide important information on the health effects of cocoa extract and multivitamin supplementation in older U.S. adults. Clinical Trials Registration: clinicaltrials.gov #NCT02422745.
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Affiliation(s)
- Pamela M Rist
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Howard D Sesso
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Lisa G Johnson
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Aaron K Aragaki
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Lu Wang
- Epidemiology, Janssen Research & Development, LLC, Titusville, NJ, USA
| | - Susanne Rautiainen
- Department of Global Public Health, Karolinska Institute, Stockholm, Sweden
| | - Aditi Hazra
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Deirdre K Tobias
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Meryl S LeBoff
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Georgina Friedenberg
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Trisha Copeland
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Allison Clar
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Lesley F Tinker
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Rebecca P Hunt
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shari S Bassuk
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ara Sarkissian
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Douglas C Smith
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eduardo Pereira
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - William R Carrick
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emily S Wion
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jennifer Schoenberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Garnet L Anderson
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - JoAnn E Manson
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Morimoto Y, Takahashi H, Arita A, Itakura H, Fujii M, Sekido Y, Hata T, Fujino S, Ogino T, Miyoshi N, Uemura M, Matsuda C, Yamamoto H, Mizushima T, Doki Y, Eguchi H. High postoperative carcinoembryonic antigen as an indicator of high-risk stage II colon cancer. Oncol Lett 2022; 23:167. [PMID: 35414828 PMCID: PMC8988258 DOI: 10.3892/ol.2022.13287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/17/2022] [Indexed: 11/30/2022] Open
Abstract
Postoperative carcinoembryonic antigen (post-CEA) has recently been reported to be a reliable prognostic factor for colon cancer. However, most clinicians decide whether or not to conduct adjuvant chemotherapy (AC) for stage II colon cancer according to major guidelines, which do not include post-CEA in their high-risk criteria. The present study aimed to assess post-CEA in stage II colon cancer for which the significance of AC is unknown. The present study analyzed 199 consecutive patients with stage II colon cancer who underwent curative surgery between January 2007 and December 2016. The CEA value was considered high when it was ≥5.0 ng/ml. The prognostic value of high post-CEA values was assessed. Overall, 19 patients exhibited high post-CEA levels. Kaplan-Meier survival curve analysis demonstrated that patients with high post-CEA levels had significantly worse relapse-free survival (RFS) and overall survival (OS) than those with normal post-CEA [RFS, 63.5 (high post-CEA) vs. 88.0% (normal post-CEA), P=0.003; OS, 76.5 (high post-CEA) vs. 96.8% (normal post-CEA), P<0.001]. Multivariate analysis demonstrated that high post-CEA remained a significant independent risk factor for worse RFS [hazard ratio (HR), 3.98; P=0.006]. The same was also demonstrated for patients without AC (HR, 5.43; P=0.008). To the best of our knowledge, the present study was the first to demonstrate that high post-CEA levels may be an indicator of high-risk stage II colon cancer, even for patients without AC. These results highlight the need for a multicenter prospective study.
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Affiliation(s)
- Yoshihiro Morimoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Asami Arita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Itakura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Makoto Fujii
- Department of Mathematical Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shiki Fujino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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Helical tomotherapy for asymptomatic chemotherapy-refractory or -unfit multiple (3 or more) metastases. Rep Pract Oncol Radiother 2022; 27:125-133. [PMID: 35402042 PMCID: PMC8989439 DOI: 10.5603/rpor.a2022.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/16/2022] [Indexed: 11/26/2022] Open
Abstract
Background Despite chemotherapy innovations, prognosis of patients with chemotherapy-refractory or -unfit multiple metastases (CRMM/CUMM) remains poor. In this prospective study, the efficacy and toxicity of helical tomotherapy for CRMM/CUMM were evaluated. Materials and methods Between 2014 and 2020, asymptomatic patients with CRMM/CUMM with ≥ 3 lesions and no prior radiotherapy of the targets were enrolled. Patients who had intolerable toxicities to chemotherapy and those who refused chemotherapy were included in the CRMM and CUMM groups, respectively. Prostate cancer patients and patients with metastases mainly localized in the liver, lung, or brain were excluded. By helical tomotherapy, up to 10 lesions per patient were irradiated in order of volume. The standard dose was 50–60 Gy in 25–30 fractions. Results Forty-five patients (median age, 63 years; 35 CRMM/10 CUMM) were enrolled. Primary tumors included lung, gynecological, and gastrointestinal cancers. The most frequently treated targets were lymph node metastases, followed by peritoneal/pleural disseminations and bone tumors. The 1-year survival rate was 51% (median, 12.5 months). In the 35 patients with CRMM, the median survival time was 12.5 months, and the median pre-radiation chemotherapy period was 8.8 months (p > 0.05). The 6-month target control rate was 78%. Acute adverse events (grade ≥ 2) occurred in 33 patients: hematologic toxicities in 23, dermatitis in 6, and others in 8. Late grade ≥ 2 toxicities occurred in 6 patients: pneumonitis in 4 and gastric hemorrhage in 2. Conclusion Tomotherapy for CRMM/CUMM resulted in median survival times > 1 year. This treatment should be investigated further in larger prospective studies.
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Beretta F, Huang YF, Punga AR. Towards Personalized Medicine in Myasthenia Gravis: Role of Circulating microRNAs miR-30e-5p, miR-150-5p and miR-21-5p. Cells 2022; 11:cells11040740. [PMID: 35203389 PMCID: PMC8870722 DOI: 10.3390/cells11040740] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/11/2022] [Accepted: 02/16/2022] [Indexed: 11/25/2022] Open
Abstract
Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable skeletal muscle weakness with a fluctuating unpredictable course. One main concern in MG is the lack of objective biomarkers to guide individualized treatment decisions. Specific circulating serum microRNAs (miRNAs) miR-30e-5p, miR-150-5p and miR-21-5p levels have been shown to correlate with clinical course in specific MG patient subgroups. The aim of our study was to better characterize these miRNAs, regardless of the MG subgroup, at an early stage from diagnosis and determine their sensitivity and specificity for MG diagnosis, as well as their predictive power for disease relapse. Serum levels of these miRNAs in 27 newly diagnosed MG patients were compared with 245 healthy individuals and 20 patients with non-MG neuroimmune diseases. Levels of miR-30e-5p and miR-150-5p significantly differed between MG patients and healthy controls; however, no difference was seen compared with patients affected by other neuroimmune diseases. High levels of miR-30e-5p predicted MG relapse (p = 0.049) with a hazard ratio of 2.81. In summary, miR-150-5p is highly sensitive but has low specificity for MG, while miR-30e-5p has the greatest potential as a predictive biomarker for the disease course in MG, regardless of subgroup.
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Affiliation(s)
- Francesca Beretta
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
| | - Yu-Fang Huang
- Department of Medical Sciences, Clinical Neurophysiology, Uppsala University, 75185 Uppsala, Sweden;
| | - Anna Rostedt Punga
- Department of Medical Sciences, Clinical Neurophysiology, Uppsala University, 75185 Uppsala, Sweden;
- Correspondence:
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Chhibber A, Huang L, Zhang H, Xu J, Cristescu R, Liu X, Mehrotra DV, Shen J, Shaw PM, Hellmann MD, Snyder A. Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types. Immunity 2022; 55:56-64.e4. [PMID: 34986342 DOI: 10.1016/j.immuni.2021.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 10/21/2021] [Accepted: 12/08/2021] [Indexed: 12/14/2022]
Abstract
We evaluated the impact of class I and class II human leukocyte antigen (HLA) genotypes, heterozygosity, and diversity on the efficacy of pembrolizumab. Seventeen pembrolizumab clinical trials across eight tumor types and one basket trial in patients with advanced solid tumors were included (n > 3,500 analyzed). Germline DNA was genotyped using a custom genotyping array. HLA diversity (measured by heterozygosity and evolutionary divergence) across class I loci was not associated with improved response to pembrolizumab, either within each tumor type evaluated or across all patients. Similarly, HLA heterozygosity at each class I and class II gene was not associated with response to pembrolizumab after accounting for the number of tests conducted. No conclusive association between HLA genotype and response to pembrolizumab was identified in this dataset. Germline HLA genotype or diversity alone is not an important independent determinant of response to pembrolizumab and should not be used for clinical decision-making in patients treated with pembrolizumab.
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Affiliation(s)
- Aparna Chhibber
- Department of Biomarker and Genome Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Lingkang Huang
- Department of Biostatistics and Research Decision Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Hong Zhang
- Department of Biostatistics and Research Decision Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Jialin Xu
- Department of Biostatistics and Research Decision Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Razvan Cristescu
- Department of Biomarker and Genome Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Xiaoqiao Liu
- Department of Biomarker and Genome Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Devan V Mehrotra
- Department of Biostatistics and Research Decision Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Judong Shen
- Department of Biostatistics and Research Decision Sciences, Merck & Co., Kenilworth, NJ 07033, USA
| | - Peter M Shaw
- Department of Biomarker and Genome Sciences, Merck & Co., Kenilworth, NJ 07033, USA.
| | - Matthew D Hellmann
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
| | - Alexandra Snyder
- Department of Medical Oncology, Merck & Co., Kenilworth, NJ 07033, USA.
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Li J, Jung SH. Sample size calculation for clustered survival data under subunit randomization. LIFETIME DATA ANALYSIS 2022; 28:40-67. [PMID: 34716530 DOI: 10.1007/s10985-021-09538-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 10/08/2021] [Indexed: 06/13/2023]
Abstract
Each cluster consists of multiple subunits from which outcome data are collected. In a subunit randomization trial, subunits are randomized into different intervention arms. Observations from subunits within each cluster tend to be positively correlated due to the shared common frailties, so that the outcome data from a subunit randomization trial have dependency between arms as well as within each arm. For subunit randomization trials with a survival endpoint, few methods have been proposed for sample size calculation showing the clear relationship between the joint survival distribution between subunits and the sample size, especially when the number of subunits from each cluster is variable. In this paper, we propose a closed form sample size formula for weighted rank test to compare the marginal survival distributions between intervention arms under subunit randomization, possibly with variable number of subunits among clusters. We conduct extensive simulations to evaluate the performance of our formula under various design settings, and demonstrate our sample size calculation method with some real clinical trials.
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Affiliation(s)
- Jianghao Li
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, 27705, USA
| | - Sin-Ho Jung
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, 27705, USA.
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Pilling S, Clarke K, Parker G, James K, Landau S, Weaver T, Razzaque R, Craig T. Open Dialogue compared to treatment as usual for adults experiencing a mental health crisis: Protocol for the ODDESSI multi-site cluster randomised controlled trial. Contemp Clin Trials 2021; 113:106664. [PMID: 34958932 PMCID: PMC8844585 DOI: 10.1016/j.cct.2021.106664] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/17/2021] [Accepted: 12/21/2021] [Indexed: 11/24/2022]
Abstract
Background ‘Open Dialogue’ is a social network model of crisis and continuing mental healthcare which involves elements of service delivery such as immediate response and a style of therapeutic meeting called network meetings. Although there are indications from non-randomised studies that it may help people in their recovery from severe mental health crises and improve long-term outcomes, this has yet to be tested in a randomised controlled trial. Methods This paper outlines the protocol for a multi-site cluster-randomised control trial assessing the clinical and cost-effectiveness of Open Dialogue compared to treatment as usual (TAU) for individuals presenting in crisis to six mental health services in England. The primary outcome is time to relapse, with secondary outcomes including measures of recovery and service use. Participants will be followed-up for two years, with data collected from electronic medical records and researcher-led interviews. The analysis will compare outcomes between treatment groups as well as investigating potential mediators of effect: shared decision-making and social network quality and size. Carers of a subsample of participants will be asked about their experiences of shared decision-making, carer burden, and satisfaction. Discussion This trial will provide evidence of whether Open Dialogue services implemented in the English mental health system is an effective alternative to current care and may have important implications for the organization of community mental health services. Trial registration: retrospectively registered (108 participants recruited of 570 target) on 20/12/2019, ISRCTN52653325.
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Affiliation(s)
- Stephen Pilling
- Centre for Outcomes Research and Effectiveness, Department of Clinical, Health and Educational Psychology, University College London, 1-19 Torrington Pl, London WC1E 7HB, UK.
| | - Katherine Clarke
- Centre for Outcomes Research and Effectiveness, Department of Clinical, Health and Educational Psychology, University College London, 1-19 Torrington Pl, London WC1E 7HB, UK
| | - Georgie Parker
- Centre for Outcomes Research and Effectiveness, Department of Clinical, Health and Educational Psychology, University College London, 1-19 Torrington Pl, London WC1E 7HB, UK
| | - Kirsty James
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London SE5 8AB, UK
| | - Sabine Landau
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London SE5 8AB, UK
| | - Timothy Weaver
- Middlesex University, Department of Mental Health & Social Work, Room TG70, Ground Floor Town Hall, School of Health and Education, The Burroughs, London NW4 4BT, UK
| | - Russell Razzaque
- North East London Foundation Trust, Research and Development Department, 1st Floor Maggie Lilley Suite, Goodmayes Hospital, Barley Lane Ilford, IG3 8XJ London, UK
| | - Thomas Craig
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London SE5 8AB, UK
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Tang Y. Complex survival trial design by the product integration method. Stat Med 2021; 41:798-814. [PMID: 34908180 DOI: 10.1002/sim.9256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 09/29/2021] [Accepted: 10/23/2021] [Indexed: 11/09/2022]
Abstract
Nonproportional hazards (NPHs) are often observed in survival trials such as the immunotherapy cancer trials. Under NPH, the classical log-rank test can be inefficient, and the estimated hazards ratio from the Cox model is difficult to interpret. The weighted log-rank test, and the tests for comparing the restricted mean survival time or the milestone survival become increasingly popular in handling NPH. The sample size calculation for these tests may require high-dimensional numerical integration. We present a sample size determination method for survival trials via product integration on the basis of a continuous-time multistate Markov model. The main challenge of the method lies in the design of the multistate model under a complex NPH pattern, and this is illustrated for NPH induced by delayed effect with individual heterogeneity in the lag duration, cure fractions, and treatment switching due to disease progression or noncompliance. Numerical examples are presented to demonstrate the accuracy of the proposed method. We obtain the following findings. The powers of the tests for milestone survival and RMST depend on both the trial duration and milestone timepoint, and may not increase as the milestone timepoint increases. If the milestone timepoint is appropriately chosen, the RMST test can be more powerful than the conventional log-rank test in the presence of diminishing treatment effect or in the proportional hazards cure model. In general, the RMST test yields lower power than a proper Fleming-Harrington weighted log-rank test.
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Affiliation(s)
- Yongqiang Tang
- Department of Biometrics, Grifols, Research Triangle Park, North Carolina
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40
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Phadnis MA, Mayo MS. Sample size calculation for two-arm trials with time-to-event endpoint for nonproportional hazards using the concept of Relative Time when inference is built on comparing Weibull distributions. Biom J 2021; 63:1406-1433. [PMID: 34272897 PMCID: PMC8497393 DOI: 10.1002/bimj.202000043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 01/23/2021] [Accepted: 03/14/2021] [Indexed: 11/07/2022]
Abstract
Sample size calculations for two-arm clinical trials with a time-to-event endpoint have traditionally used the assumption of proportional hazards (PH) or the assumption of exponentially distributed survival times. Available software provides methods for sample size calculation using a nonparametric logrank test, Schoenfeld's formula for Cox PH model, or parametric calculations specific to the exponential distribution. In cases where the PH assumption is not valid, the first-choice method is to compute sample size assuming a piecewise linear survival curve (Lakatos approach) for both the control and treatment arms with judiciously chosen cut-points. Recent advances in literature have used the assumption of Weibull distributed times for single-arm trials, and, newer methods have emerged that allow sample size calculations for two-arm trials using the assumption of proportional time (PT) while considering non-PH. These methods, however, always assume an instantaneous effect of treatment relative to control requiring that the effect size be defined by a single number whose magnitude is preserved throughout the trial duration. Here, we consider the scenarios where the hypothesized benefit of treatment relative to control may not be constant giving rise to the notion of Relative Time (RT). By assuming that survival times for control and treatment arm come from two different Weibull distributions with different location and shape parameters, we develop the methodology for sample size calculation for specific cases of both non-PH and non-PT. Simulations are conducted to assess the operation characteristics of the proposed method and a practical example is discussed.
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Affiliation(s)
- Milind A. Phadnis
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Matthew S. Mayo
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Crombé A, Cousin S, Spalato-Ceruso M, Le Loarer F, Toulmonde M, Michot A, Kind M, Stoeckle E, Italiano A. Implementing a Machine Learning Strategy to Predict Pathologic Response in Patients With Soft Tissue Sarcomas Treated With Neoadjuvant Chemotherapy. JCO Clin Cancer Inform 2021; 5:958-972. [PMID: 34524884 DOI: 10.1200/cci.21.00062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Neoadjuvant chemotherapy (NAC) has been increasingly used in patients with locally advanced high-risk soft tissue sarcomas in the past decade, but definition and prognostic impact of a good histologic response (GHR) are lacking. Our aim was to investigate which histologic feature from the post-NAC surgical specimen independently correlated with metastatic relapse-free survival (MFS) in combination with clinical, radiologic, and pathologic features using a machine learning approach. METHODS This retrospective study included 175 consecutive patients (median age: 59 years, 75 women) with resectable disease, treated with anthracycline-based NAC between 1989 and 2015 in our sarcoma reference center, and with quantitative histopathologic analysis of the surgical specimen. The outcome of interest was the MFS. A multimodel, multivariate survival analysis was used to define GHR. The added prognostic value of GHR was investigated through the comparisons with the standard model (including histologic grade, size, and depth) and SARCULATOR nomogram using concordance indices (c-index) and Monte-Carlo cross-validation. RESULTS Seventy-two patients (72 of 175, 41.1%) had a metastatic relapse. Stepwise Cox regression, random survival forests, and least absolute shrinkage and selection operator-penalized Cox regression all converged toward the same definition for GHR, ie, < 5% stainable tumor cells. The five-year MFS probability was 1 (95% CI, 1 to 1) in patients with GHR versus 0.73 (95% CI, 0.65 to 0.81) in patients without GHR (log-rank P = .0122). The final prognostic model incorporating the GHR was significantly better than the standard model and SARCULATOR (average c-index in testing sets = 0.72 [95% CI, 0.61 to 0.82] v 0.57 [95% CI, 0.44 to 0.70] and 0.54 [95% CI, 0.45 to 0.64], respectively; P = .0414 and .0091). CONCLUSION Histologic response to NAC improves the prediction of MFS in patients with soft tissue sarcoma and represents a possible end point in future studies exploring innovative regimens in the neoadjuvant setting.
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Affiliation(s)
- Amandine Crombé
- Department of Oncological Imaging, Institut Bergonié, Bordeaux, France.,Mathematical Modeling for Oncology Team, Inria Bordeaux Sud-Ouest, Talence, France.,Bordeaux University, Bordeaux, France
| | - Sophie Cousin
- Early Phase Trials and Sarcoma Units, Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | - Mariella Spalato-Ceruso
- Early Phase Trials and Sarcoma Units, Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | - François Le Loarer
- Bordeaux University, Bordeaux, France.,Department of Pathology, Institut Bergonié, Bordeaux, France
| | - Maud Toulmonde
- Early Phase Trials and Sarcoma Units, Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | - Audrey Michot
- Bordeaux University, Bordeaux, France.,Department of Oncologic Surgery, Institut Bergonié, Bordeaux, France
| | - Michèle Kind
- Department of Oncological Imaging, Institut Bergonié, Bordeaux, France
| | - Eberhard Stoeckle
- Department of Oncologic Surgery, Institut Bergonié, Bordeaux, France
| | - Antoine Italiano
- Bordeaux University, Bordeaux, France.,Early Phase Trials and Sarcoma Units, Department of Medical Oncology, Institut Bergonié, Bordeaux, France
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Mukosha M, Kaonga P, Kapembwa KM, Musonda P, Vwalika B, Lubeya MK, Jacobs C. Modelling mortality within 28 days among preterm infants at a tertiary hospital in Lusaka, Zambia: a retrospective review of hospital-based records. Pan Afr Med J 2021; 39:69. [PMID: 34422192 PMCID: PMC8363965 DOI: 10.11604/pamj.2021.39.69.27138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/05/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction globally, almost half of all deaths in children under five years of age occur among neonates. We investigated the predictors of mortality within 28 days among preterm infants at a tertiary hospital in Lusaka, Zambia. Methods we reviewed admission records linked to birth, mortality, and hospital discharge from 1st January 2018 to 30th September 2019. Information was retrieved with a follow-up period of 28 days post-delivery to discharge/mortality. We used the Weibull hazards regression to establish the best predictor model for mortality among the neonates. Results a total of 3237 case records of women with a median age of 27 years (IQR, 22-33) were included in the study, of which 971 (30%) delivered term infants and 2267 (70%) preterm infants. The overall median survival time of the infants was 98 hours (IQR, 34-360). Preterm birth was not associated with increased hazards of mortality compared to term birth (p=0.078). Being in the Kangaroo Mother Care compared to Neonatal Intensive Care Unit (NICU), and a unit increase in birth weight were independently associated with reduced hazards of mortality. On the other hand, having hypoxic-ischemic encephalopathy, experiencing difficulty in feeding and vaginal delivery compared to caesarean section independently increased the hazards of mortality. Conclusion having hypoxic-ischemic encephalopathy, vaginal delivery, and experiencing difficulty in feeding increases the risk of mortality among neonates. Interventions to reduce neonatal mortality should be directed on these factors in this setting.
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Affiliation(s)
- Moses Mukosha
- Department of Pharmacy, University of Zambia, Lusaka, Zambia.,School of Public Health, University of Zambia, Lusaka, Zambia
| | - Patrick Kaonga
- School of Public Health, University of Zambia, Lusaka, Zambia
| | | | - Patrick Musonda
- School of Public Health, University of Zambia, Lusaka, Zambia
| | - Bellington Vwalika
- Department of Obstetrics and Gynecology, University of Zambia, Lusaka, Zambia
| | - Mwansa Ketty Lubeya
- Department of Obstetrics and Gynecology, University of Zambia, Lusaka, Zambia.,Young Emerging Scientists Zambia, Lusaka, Zambia
| | - Choolwe Jacobs
- School of Public Health, University of Zambia, Lusaka, Zambia
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van Eijk RPA, Nikolakopoulos S, Roes KCB, Kendall L, Han SS, Lavrov A, Epstein N, Kliest T, de Jongh AD, Westeneng HJ, Al-Chalabi A, Van Damme P, Hardiman O, Shaw PJ, McDermott CJ, Eijkemans MJC, van den Berg LH. Challenging the Established Order: Innovating Clinical Trials for Amyotrophic Lateral Sclerosis. Neurology 2021; 97:528-536. [PMID: 34315786 PMCID: PMC8456357 DOI: 10.1212/wnl.0000000000012545] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/09/2021] [Indexed: 11/15/2022] Open
Abstract
Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS—(1) patient selection and (2) analytical strategy—and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.
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Affiliation(s)
- Ruben P A van Eijk
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands. .,Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Stavros Nikolakopoulos
- Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Kit C B Roes
- Department of Health Evidence, Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands
| | | | - Steve S Han
- Neurosciences, Takeda Pharmaceuticals, Cambridge, USA.,Discovery Medicine, GlaxoSmithKline R&D, Upper Providence, USA
| | - Arseniy Lavrov
- Clinical Development, Novartis Gene Therapies, London, UK.,Clinical Translational Medicine, Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex, UK
| | - Noam Epstein
- Discovery Medicine, GlaxoSmithKline R&D, Upper Providence, USA
| | - Tessa Kliest
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Adriaan D de Jongh
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Henk-Jan Westeneng
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ammar Al-Chalabi
- King's College London, London, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, UK.,Department of Neurology, King's College Hospital, London, UK
| | - Philip Van Damme
- Department of Neurosciences, Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute, Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Orla Hardiman
- Department of Neurology, National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland.,FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Pamela J Shaw
- Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, Sheffield, UK
| | - Christopher J McDermott
- Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, Sheffield, UK
| | - Marinus J C Eijkemans
- Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Leonard H van den Berg
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands
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He Y, Timofeeva M, Zhang X, Xu W, Li X, Din FVN, Svinti V, Farrington SM, Campbell H, Dunlop MG, Theodoratou E. Colorectal cancer risk variants rs10161980 and rs7495132 are associated with cancer survival outcome by a recessive mode of inheritance. Int J Cancer 2021; 148:2774-2778. [PMID: 33411955 PMCID: PMC8614120 DOI: 10.1002/ijc.33465] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/09/2020] [Accepted: 11/19/2020] [Indexed: 01/13/2023]
Abstract
Previous studies using additive genetic models failed to identify robust evidence of associations between colorectal cancer (CRC) risk variants and survival outcomes. However, additive models can be prone to false negative detection if the underlying inheritance mode is recessive. Here, we tested all currently known CRC-risk variants (n = 129) in a discovery analysis of 5675 patients from a Scottish cohort. Significant associations were then validated in 2474 CRC cases from UK Biobank. We found that the TT genotype of the intron variant rs7495132 in the CRTC3 gene was associated with clinically relevant poorer CRC-specific survival in both the discovery (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.41-2.74, P = 6.1 × 10-5 ) and validation analysis (HR = 1.69, 95% CI = 1.03-2.79, P = .038). In addition, the GG genotype of rs10161980 (intronic variant of AL139383.1 lncRNA) was associated with worse overall survival in the discovery cohort (HR = 1.24, 95% CI = 1.10-1.39, P = 3.4 × 10-4 ) and CRC-specific survival in the validation cohort (HR = 1.26, 95% CI = 1.01-1.56, P = .040). Our findings show that common genetic risk factors can also influence CRC survival outcome.
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Affiliation(s)
- Yazhou He
- Department of Oncology, West China School of Public Health and West China Fourth HospitalSichuan UniversityChengduPeople's Republic of China
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Danish Institute for Advanced Study (DIAS), Department of Public HealthUniversity of Southern DenmarkOdenseDenmark
| | - Xiaomeng Zhang
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
| | - Wei Xu
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
| | - Xue Li
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
- School of Public HealthZhejiang UniversityHangzhouPeople's Republic of China
| | - Farhat V. N. Din
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
| | - Victoria Svinti
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
| | - Susan M. Farrington
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
| | - Harry Campbell
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
| | - Malcolm G. Dunlop
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
| | - Evropi Theodoratou
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General HospitalThe University of EdinburghEdinburghUK
- Centre for Global Health, Usher InstituteThe University of EdinburghEdinburghUK
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45
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Hu C. Statistical methods for survival trial design—With applications to cancer clinical trials using R by JianrongWu, CRC Press, 2018, ISBN 9780367734329. Biometrics 2021. [DOI: 10.1111/biom.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Chen Hu
- Johns Hopkins University School of Medicine
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46
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Development of a novel CT-derived measure of cardiovascular health: the CT aortic stiffness index (CTASI). Clin Res Cardiol 2021; 110:1781-1791. [PMID: 33978816 DOI: 10.1007/s00392-021-01861-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
AIMS Aortic stiffness, measured as aortic pulse wave velocity (PWV), is a powerful predictor of cardiovascular health but is difficult to accurately obtain non-invasively. This study sought to develop a novel CT aortic stiffness index (CTASI) which incorporates both anatomical (calcification) and physiological (distensibility) aspects of aortic health. METHODS Invasive PWV and CT scans were obtained for 80 patients undergoing TAVI (cohort 1). CT data alone were obtained from an additional 238 patients (cohort 2). Aortic calcification was quantified using a modified Agatston's methodology. Distensibility-PWV was calculated from minimum and maximum ascending aorta areas. Linear regression of these values was used to construct CTASI from cohort 1. CTASI was then calculated for cohort 2 who were prospectively followed-up. RESULTS CTASI correlated with invasive PWV (rho = 0.47, p < 0.01) with a higher correlation coefficient than distensibility-PWV (rho = 0.35, p < 0.01) and aortic calcification (rho = 0.36, p < 0.01). Compared to invasive PWV, CTASI had a good accuracy as a diagnostic test (AOC 0.72 [95% CI 0.61-0.84]), superior to aortic calcification and distensibility-PWV alone (χ2 = 0.82, p = 0.02). There were 61 deaths during a median follow-up of 771 days (95% CI 751.4-790.5). CTASI was able to predict 1-year mortality (OR 2.58, 95% CI 1.18-5.61, p = 0.02) and Kaplan-Meier survival (log-rank p = 0.03). CONCLUSION CTASI is a stronger measure of aortic stiffness than aortic calcification or distensibility alone. Given the prolific use of CT scanning for assessing coronary and vascular disease, the additional calculation of CTASI during these scans could provide an important direct measurement of vascular health and guide pharmacological therapy.
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47
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Bignotto M, Dei Cas M, Paroni R, Bianco E, Zermiani P, Gangale MG, Zadro V, Maregatti M, Piagnani A, Russo A, Baldassarre D, Folli F, Battezzati PM, Zuin M. CA.ME.LI.A. An epidemiological study on the prevalence of CArdiovascular, MEtabolic, LIver and Autoimmune diseases in Northern Italy. Nutr Metab Cardiovasc Dis 2021; 31:1416-1426. [PMID: 33814235 DOI: 10.1016/j.numecd.2021.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) is a cross-sectional, epidemiological study performed between 2009-2011 in Abbiategrasso (Milan, Italy) to estimate the prevalence of cardiovascular risk factors, metabolic syndrome, liver and autoimmune diseases in the general adult population. This report focuses on the description and presentation of baseline characteristics of the population. METHODS AND RESULTS Citizens were randomly selected from the city electoral registers (n = 30903), yielding a sample of 2554 subjects (M = 1257, F = 1297; age, 47 ± 15 yrs; range 18-77 yrs). Men had higher prevalence of overweight or obesity (60.8% vs 41.6%; p < 0.0001) and greater thickness of visceral adipose tissue (40 ± 19 vs 27 ± 17 mm; p < 0.0001); no gender difference was found in subcutaneous adipose tissue thickness. Men also showed higher levels of serum triglycerides, γ-GT, fasting blood glucose, insulin and Homa-IR Index, while HDL, CRP, and prevalence of elevated (>5.0 mg/L) CRP were lower. Compared to normal weight men, risk-ratio (RR) of CRP elevation was 1.32 (ns) in overweight and 2.68 (p < 0.0001) in obese subjects. The corresponding figures in females were 2.68 (p < 0.0001) and 5.18 (p < 0.0001). Metabolic syndrome was more frequent in men (32.7% vs 14.5%; RR: 2.24, p < 0.0001). Interadventitia common carotid artery diameter was higher in men and increased with age and BMI. CONCLUSIONS The present study reports on the overall characteristics of a large population from Northern Italy. It aims to identify the associations among cardiovascular risk factors to prevent their development and progression, improve healthy lifestyle and identify subjects liable to pharmacological interventions.
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Affiliation(s)
- Monica Bignotto
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Michele Dei Cas
- Clinical Biochemistry and Mass Spectrometry, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Rita Paroni
- Clinical Biochemistry and Mass Spectrometry, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Elena Bianco
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Paola Zermiani
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Maria G Gangale
- ASST Ovest Milanese, via Papa Giovanni Paolo II, Legnano, Milan, Italy
| | - Valentina Zadro
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Margherita Maregatti
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Alessandra Piagnani
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy
| | - Antonio Russo
- Epidemiology Unit, Agency for Health Protection of Milan, Corso Italia 19, 20122, Milan, Italy
| | - Damiano Baldassarre
- Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy.
| | - Pier Maria Battezzati
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy
| | - Massimo Zuin
- Liver and Gastroenterology Unit, Department of Health Sciences, Universita' degli Studi di Milano, Milan, Italy; ASST Santi Paolo e Carlo, University Hospital San Paolo, via A. Di Rudini', Milan, Italy.
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Nguyen LT, Nguyen HV, Do DH, Nguyen KT, Do AT, Pham HH, Nguyen CD. Survival in resectable pancreatic ductal adenocarcinoma with para-aortic lymph node dissection: A retrospective study in Vietnamese population. Ann Med Surg (Lond) 2021; 65:102361. [PMID: 34026099 PMCID: PMC8120866 DOI: 10.1016/j.amsu.2021.102361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/16/2021] [Accepted: 04/25/2021] [Indexed: 02/07/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) has a high recurrence rate and poor outcome. Lymph node (LN) metastasis, especially para-aortic LN (PALN), is an important prognostic factor. PALN assessment through sampling with frozen-section analysis is a validated method. Our aim was to evaluate the prognostic impact of PALN on overall survival (OS) in patients who underwent standard pancreaticoduodenectomy, lymphadenectomy with PALN sampling, as well as to identify other prognostic factors for survival. Methods Our retrospective study included 89 PDAC patients undergoing radical resection with PALN sampling. The patients were classified into PALN(+) (n = 11) and PALN(-) (n = 78). Univariate and multivariate analyses of 1-year and 3-year OS and Kaplan-Meier model were used. Results OS after 1-year for PALN(+) and PALN(-) was 18.2 and 56.4%, after 3-year was 15.4% and 0%, respectively. Tumor differentiation, LN metastasis (LN(-), LN(+) PALN(-), LN(+) PALN(+)) were significant prognostic factors in both univariate and multivariate analyses for 1-year OS, and neural invasion (PN) was the solely significant factor for 3-year OS (p < 0.05). Kaplan-Meier estimate showed that OS of PALN(+) and PN (+) was significantly lower than the negative group, respectively (p < 0.05). No statistical difference in OS was seen between LN(-) and LN(+) PALN(-); and between LN(+) PALN(-) and PALN(+) (p = 0.107). Patients with PN (-) PALN(+) had similar OS compared to PN (+) PALN(-) (p > 0.05). Conclusion PDAC had a poor outcome despite treatment with radical resection. Further follow-up should be conducted to determine the role of surgery in PALN(+)and PN invasion.
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Affiliation(s)
- Lan Thi Nguyen
- Department of Hepatobiliary Surgery, VietDuc University Hospital, Hanoi, Viet Nam
| | - Hung Van Nguyen
- Department of Oncology and Palliative Care, Hanoi Medical University Hospital, Hanoi, Viet Nam
| | - Dang Hai Do
- Department of General Surgery, Hanoi Medical University, Hanoi, Viet Nam
| | - Khiem Thanh Nguyen
- Gastrointestinal and Hepato - Biliary - Pancreatic Surgery Department, Bach Mai Hospital, Hanoi, Viet Nam
| | - Anh Tuan Do
- Department of Hepatobiliary Surgery, VietDuc University Hospital, Hanoi, Viet Nam
| | - Ha Hoang Pham
- Digestive Surgery Department, VietDuc University Hospital, Hanoi, Viet Nam
| | - Chinh Duc Nguyen
- Department of Septic Surgery, VietDuc University Hospital, Hanoi, Viet Nam
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Scott JV, Garnett CE, Kanwar MK, Stockbridge NL, Benza RL. Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials. Am J Respir Crit Care Med 2021; 203:726-736. [PMID: 32937078 DOI: 10.1164/rccm.202002-0357oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Rationale: Event-driven primary endpoints are increasingly used in pulmonary arterial hypertension clinical trials, substantially increasing required sample sizes and trial lengths. The U.S. Food and Drug Administration advocates the use of prognostic enrichment of clinical trials by preselecting a patient population with increased likelihood of experiencing the trial's primary endpoint.Objectives: This study compares validated clinical scales of risk (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, the French score, and Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management [REVEAL] 2.0) to identify patients who are likely to experience a clinical worsening event for trial enrichment.Methods: Baseline data from three pulmonary arterial hypertension clinical trials (AMBITION [a Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension], SERAPHIN [Study of Macitentan on Morbidity and Mortality in Patients with Symptomatic Pulmonary Arterial Hypertension], and GRIPHON [Selexipag in Pulmonary Arterial Hypertension]) were pooled and standardized. Receiver operating curves were used to measure each algorithm's performance in predicting clinical worsening within the pooled placebo cohort. Power simulations were conducted to determine sample size and treatment time reductions for multiple enrichment strategies. A cost analysis was performed to illustrate potential financial savings by applying enrichment to GRIPHON.Measurements and Main Results: All risk algorithms were compared using area under the receiver operating curve and substantially outperformed prediction per New York Heart Association Functional Class. The REVEAL 2.0's risk grouping provided the greatest time and sample size savings in AMBITION and GRIPHON for all enrichment strategies but lacked appropriate inputs (i.e., N-terminal-proB-type natriuretic peptide) to perform as well in SERAPHIN. Cost analysis applied to GRIPHON demonstrated the greatest financial benefit by enrolling patients with a REVEAL score ≥8.Conclusions: This preliminary study demonstrates the feasibility of risk algorithms for pulmonary arterial hypertension trial enrichment and a need for further investigation.
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Affiliation(s)
- Jacqueline V Scott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania.,Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; and
| | - Christine E Garnett
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; and
| | - Manreet K Kanwar
- Cardiovascular Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Norman L Stockbridge
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; and
| | - Raymond L Benza
- Cardiovascular Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
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Regassa LD, Tola A. Magnitude and predictors of hospital admission, readmission, and length of stay among patients with type 2 diabetes at public hospitals of Eastern Ethiopia: a retrospective cohort study. BMC Endocr Disord 2021; 21:74. [PMID: 33866969 PMCID: PMC8054433 DOI: 10.1186/s12902-021-00744-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/12/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Type 2 Diabetes (T2D) represents one of the leading causes for hospital admissions and outpatient visits. Hence, T2D continuously imposes a significant burden to healthcare systems. The aim of this study was to assess predictors of hospital admission, readmission rates, and length of hospital stay among T2D patients in government hospitals of Eastern Ethiopia from 2013 to 2017. METHODS This study utilized retrospective data from a cohort of T2D patients following their treatment in government hospitals in Harari regional state of Ethiopia. Predictor of hospital admission was determined using parametric survival analysis methods. The readmission rate and length of hospital stay were determined by Poisson regression and mixed effect Poisson regression, respectively. All association were performed at 95% confidence level. Significance of association with determinants was reported using the hazard rate for hospital admission, and the incidence rate for readmission and length of hospital stay. Optimal model for each outcome was selected by using information criteria after fitness was checked. RESULTS The hospital admission rate for T2D patients was 9.85 (95%CI: 8.32, 11.66) per 1000-person-year observation. Alcohol drinking, inactive lifestyle, being a rural resident, history of comorbidities, and experiencing chronic diabetes complications were predictors of hospital admission. Seventy-one (52.2%) of the admitted patients had a history of readmission. Readmission rate was increased by being female, duration of disease, inactive lifestyle, having BMI greater than 29.9 kg/m2, and higher blood glucose. The median time of hospital stay for admitted patients was 18 (IQR:7). The length of hospital stay was longer among females, patients with the history of insulin administration, and higher blood glucose. CONCLUSION Multiple and complex factors were contributing for high diabetes admission and readmission rates as well as for longer in-hospital duration among T2D patients in Harari regional state. Socio-demographic characteristics (sex, place of residence), behavioral factors (alcohol intake, lifestyle), and medical conditions (longer duration of disease, comorbidities, chronic diabetes complications, higher blood glucose level, and treatment modality) were significant determinants of hospital admission, readmission and longer hospital stay among T2D patients.
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Affiliation(s)
- Lemma Demissie Regassa
- Department of Epidemiology and Biostatistics, College of Health and Medical Sciences, Haramaya University, P. O. Box 135, Dire Dawa, Ethiopia
| | - Assefa Tola
- Department of Epidemiology and Biostatistics, College of Health and Medical Sciences, Haramaya University, P. O. Box 135, Dire Dawa, Ethiopia
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