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Immunophenotypic changes in the tumor and tumor microenvironment during progression to multiple myeloma
Investigation of the cellular and molecular mechanisms of disease progression from precursor plasma cell disorders to active disease increases our understanding of multiple myeloma (MM) pathogenesis and supports the development of novel therapeutic strategies. In this analysis, single-cell RNA sequencing, surface protein profiling, and B lymphocyte antigen receptor profiling of unsorted, whole bone marrow (BM) mononuclear cell samples was used to study molecular changes in tumor cells and the tumor microenvironment (TME). A cell atlas of the BM microenvironment was generated from 123 subjects including healthy volunteers and patients with monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM. These analyses revealed commonalities in molecular pathways, including MYC signaling, E2F targets and interferon alpha response, that were altered during disease progression. Evidence of early dysregulation of the immune system in MGUS and SMM, which increases and impacts many cell types as the disease progresses, was found. In parallel with disease progression, population shifts in CD8 + T cells, macrophages, and classical dendritic cells were observed, and the resulting differences in CD8 + T cells and macrophages were associated with poor overall survival outcomes. Potential ligand-receptor interactions that may play a role during the transition from precursor stages to MM were identified, along with potential biomarkers of disease progression, some of which may represent novel therapeutic targets. MIF, IL15, CD320, HGF and FAM3C were detected as potential regulators of the TME by plasma cells, while SERPINA1 and BAFF (TNFSF13B) were found to have the highest potential to contribute to the downstream changes observed between precursor stage and MM cells. These findings demonstrate that myeloma tumorigenesis is associated with dysregulation of molecular pathways driven by gradually occurring immunophenotypic changes in the tumor and TME. Trial registration: This project has been registered at EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with protocol number NOPRODMMY0001 and EudraCT Number 2018-004443-23 on 12 December 2018.
Journal Article
Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies
Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
Journal Article
Statistical significance or clinical significance? A researcher's dilemma for appropriate interpretation of research results
It is incredibly essential that the current clinicians and researchers remain updated with findings of current biomedical literature for evidence-based medicine. However, they come across many types of research that are nonreproducible and are even difficult to interpret clinically. Statistical and clinical significance is one such difficulty that clinicians and researchers face across many instances. In simpler terms, the P value tests all hypothesis about how the data were produced (model as whole), and not just the targeted hypothesis that it is intended to test (such as a null hypothesis) keeping in mind how reliable are the of the research results. Most of the times it is misinterpreted and misunderstood as a measure to judge the results as clinically significant. Hence this review aims to impart knowledge about \"P\" value and its importance in biostatistics, also highlights the importance of difference between statistical and clinical significance for appropriate interpretation of research results.
Journal Article
Multiple myeloma
Multiple myeloma is the second most common haematological malignancy in high-income countries, and typically starts as asymptomatic precursor conditions—either monoclonal gammopathy of undetermined significance or smouldering multiple myeloma—in which initiating genetic abnormalities, such as hyperdiploidy and translocations involving the immunoglobulin heavy chain, are already present. The introduction of immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies has extended survival, but ultimately the majority of patients will die from their disease, and some from treatment-related complications. Disease progression and subsequent relapses are characterised by subclonal evolution and increasingly resistant disease. Patients with multiple myeloma usually have hypercalcaemia, renal failure, anaemia, or osteolytic bone lesions—and a detailed diagnostic investigation is needed to differentiate between symptomatic multiple myeloma that requires treatment, and precursor states. Risk stratification using both patient-specific (eg, performance status) and disease-specific (eg, presence of high-risk cytogenetic abnormalities) is important for prognosis and to define the best treatment strategy. Current research strategies include the use of minimal residual disease assays to guide therapy, refining immunotherapeutic approaches, and intercepting disease early in smouldering multiple myeloma.
Journal Article
Statistical Significance, 𝑝-Values, and the Reporting of Uncertainty
The use of statistical significance and 𝑝-values has become a matter of substantial controversy in various fields using statistical methods. This has gone as far as some journals banning the use of indicators for statistical significance, or even any reports of 𝑝-values, and, in one case, any mention of confidence intervals. I discuss three of the issues that have led to these often-heated debates. First, I argue that in many cases, 𝑝-values and indicators of statistical significance do not answer the questions of primary interest. Such questions typically involve making (recommendations on) decisions under uncertainty. In that case, point estimates and measures of uncertainty in the form of confidence intervals or even better, Bayesian intervals, are often more informative summary statistics. In fact, in that case, the presence or absence of statistical significance is essentially irrelevant, and including them in the discussion may confuse the matter at hand. Second, I argue that there are also cases where testing null hypotheses is a natural goal and where 𝑝-values are reasonable and appropriate summary statistics. I conclude that banning them in general is counterproductive. Third, I discuss that the overemphasis in empirical work on statistical significance has led to abuse of 𝑝-values in the form of 𝑝-hacking and publication bias. The use of pre-analysis plans and replication studies, in combination with lowering the emphasis on statistical significance may help address these problems.
Journal Article
P222 Evaluation of drainage and closure methods following local anaesthetic thoracoscopy (LAT): a multi-centre analysis of complications and outcomes
IntroductionLocal Anaesthetic Thoracoscopy (LAT) is a well-established procedure for evaluating unexplained exudative pleural effusions. The standard approach involves the insertion of a chest drain post-LAT, connected to an underwater seal to facilitate lung re-expansion and reduce the risk of surgical emphysema (SE).Alternative techniques include placement of a long-term indwelling pleural catheter (IPC) when indicated, connected to an underwater seal or capped, as well as primary closure of the LAT incision without drainage.AimTo evaluate different methods of incision closure and drainage following LAT, and to assess associated complications.MethodsRetrospective review of 289 patients undergoing LAT between 2022 and 2024 across three UK centres.ResultsMean age 71.5 years (range 33–92); 222 (76.8%) males. LAT was performed as a day-case procedure in 246 patients (85.1%). 31 (10.7%) had large bore drain insertion removed prior to discharge; 175 (60.6%) had IPC connected to an underwater seal until discharge; 39 (13.5%) had a capped IPC with no drainage and 44 (15.2%) had primary incision closure without drainage.6 (2.1%) intraoperative complications, none related to drainage or closure methods. 19 (6.6%) had post LAT complications within 30 days.Of the 175 with post LAT IPC and underwater seal, 3 (1.7%) had local infection, 1(0.57%) had pneumonia, 4 (2.3%) had ongoing air leak or clinically significant surgical emphysema requiring admission; 3 (1.7%) had blocked IPC and 2 (1.1%) had complications unrelated to drainage method.Of the 83 who had primary closure with or without capped IPC, 3 (3.6%) had clinically significant surgical emphysema, 1 (1.2%) slow to re-expand lung,1 (1.2%) local infection and 1(1.2%) complication unrelated to drainage method. There were no deaths related to LAT.Abstract P222 Figure 1[Image Omitted. See PDF.]ConclusionsOur study demonstrates that various drainage and incision closure techniques following LAT, performed as day-case procedures, are generally safe and associated with low complication rates. The less conventional approach - primary incision closure and no drainage – does not appear to increase the risk of clinically significant surgical emphysema (SE) compared to post LAT drainage with either a short-term chest drain or IPC. Further prospective studies are warranted to compare these techniques.
Journal Article
Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance
MGUS affects more than 5% of persons older than 70 years and shortens survival, as compared with age-matched controls. In a long-term study involving more than 1000 patients, those with IgM MGUS had a higher rate of progression to B-cell cancer than those with IgG MGUS.
Journal Article