Trajectories of recovery and dysfunction after acute illness, with implications for clinical trial design.
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ABSTRACT:
SUBMITTER: Iwashyna TJ
PROVIDER: S-EPMC3443808 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPatients who survive critical illness suffer from a significant physical disability. The impact of rehabilitation strategies on health-related quality of life is inconsistent, with population heterogeneity cited as one potential confounder. This secondary analysis aimed to (1) examine trajectories of functional recovery in critically ill patients to delineate sub-phenotypes and (2) to assess differences between these cohorts in both clinical characteristics and clinimetric properties of physical function assessment tools.MethodsTwo hundred ninety-one adult sepsis survivors were followed-up for 24 months by telephone interviews. Physical function was assessed using the Physical Component Score (PCS) of the Short Form-36 Questionnaire (SF-36) and Activities of Daily Living and the Extra Short Musculoskeletal Function Assessment (XSFMA-F/B). Longitudinal trajectories were clustered by factor analysis. Logistical regression analyses were applied to patient characteristics potentially determining cluster allocation. Responsiveness, floor and ceiling effects and concurrent validity were assessed within clusters.ResultsOne hundred fifty-nine patients completed 24 months of follow-up, presenting overall low PCS scores. Two distinct sub-cohorts were identified, exhibiting complete recovery or persistent impairment. A third sub-cohort could not be classified into either trajectory. Age, education level and number of co-morbidities were independent determinants of poor recovery (AUROC 0.743 ((95%CI 0.659-0.826), p < 0.001). Those with complete recovery trajectories demonstrated high levels of ceiling effects in physical function (PF) (15%), role physical (RP) (45%) and body pain (BP) (57%) domains of the SF-36. Those with persistent impairment demonstrated high levels of floor effects in the same domains: PF (21%), RP (71%) and BP (12%). The PF domain demonstrated high responsiveness between ICU discharge and at 6 months and was predictive of a persistent impairment trajectory (AUROC 0.859 (95%CI 0.804-0.914), p < 0.001).ConclusionsWithin sepsis survivors, two distinct recovery trajectories of physical recovery were demonstrated. Older patients with more co-morbidities and lower educational achievements were more likely to have a persistent physical impairment trajectory. In regard to trajectory prediction, the PF score of the SF-36 was more responsive than the PCS and could be considered for primary outcomes. Future trials should consider adaptive trial designs that can deal with non-responders or sub-cohort specific outcome measures more effectively.
| S-EPMC7517819 | biostudies-literature
Project description:Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.
2024-10-31 | GSE242912 | GEO
Project description:Illness Management and Recovery (IMR) is a psychosocial intervention with a recovery-oriented approach. The program has been evaluated in different settings; however evidence for the effects of IMR is still deficient. The aim of this trial was to investigate the benefits and harms of the IMR program compared with treatment as usual in Danish patients with schizophrenia or bipolar disorder.The trial was designed as a randomized, assessor-blinded, multi-center, clinical trial investigating the IMR program compared with usual treatment. 198 people diagnosed with schizophrenia or bipolar disorder participated. The primary outcome was the Global Assessment of Functioning (GAF-F) at the end of intervention and the secondary and explorative outcomes included severity of symptoms and service utilization.IMR had no significant effect on functioning, symptoms, substance use or service utilization.This randomized trial contributes to the evidence base of IMR by providing a methodological solid base for its conclusions; however the trial has some important limitations. More research is needed to get a firm answer on the effectiveness of the IMR.
| S-EPMC5886399 | biostudies-literature
Project description:The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.
| S-EPMC4708174 | biostudies-literature
Project description:Statistical efficiency can be gained in clinical trials by using composites of time-to-event outcomes when the individual component outcomes have low event rates. However, the utility of continuous composite outcome measures is not as clear. Efficiency can be either gained or lost by using a continuous composite outcome measure depending on several factors, including the strength of correlation between the component outcomes and the size of the treatment effect on each component. In this article we review these concepts from the standpoint of planning a new trial. Statistical properties of composites formed from normally distributed continuous outcomes are discussed. An example dataset is used to demonstrate concepts and complete mathematical details are provided. Finally, a conceptual model for clinical trial design with continuous composites is proposed that could be used as a guide to evaluate the utility of a continuous composite outcome in a future trial based on existing knowledge in the therapeutic area.
| S-EPMC7530289 | biostudies-literature
Project description:Importance:Clinical trials are testing vaccines that target human papillomavirus 16 (HPV-16) oncoproteins for the treatment of cervical cancer regardless of the HPV type of the tumor. For patients with HPV-18-positive cancers, this strategy relies on cross-reactivity of HPV-16-reactive T cells against the HPV-18 oncoproteins. Objectives:To determine the prevalence of HPV-16 and HPV-18 metastatic cervical cancers in women enrolling in clinical trials at a US medical center and to assess whether HPV oncoprotein-targeting tumor-infiltrating lymphocytes (TILs) and T-cell receptors (TCRs) possess HPV-16/HPV-18 oncoprotein cross-reactivity. Design, Setting, and Participants:This study was conducted at the National Institutes of Health Clinical Center, a tertiary care research hospital in the United States. The HPV type of the tumors from 65 consecutive patients with cervical cancer who were evaluated for participation in clinical trials was determined by retrospective medical record review. Immunological assays testing HPV cross-reactivity were conducted on all available archived samples of oncoprotein-reactive TILs from HPV-positive tumors (n?=?16) and on a library of previously identified TCRs (n?=?10). Interventions:The HPV genotype of each patient's tumor was determined. The cross-reactivity of archived TILs and a library of TCRs was assessed. Main Outcomes and Measures:The main outcomes were the prevalence of each HPV genotype and the frequency of TILs or TCRs with HPV oncoprotein-T-cell cross-reactivity. Cross-reactivity was assessed by enzyme-linked immunospot assays and interferon-? production assays. Results:The median (range) age of 65 referred patients was 44 (24-64) years. Ethnicity was recorded for 39 of 65 patients; 35 (89.7%) were white, 3 (7.7%) were Asian, and 1 (2.6%) was American Indian/Alaskan Native. Histologic tumor subtype was recorded for 41 of 65 patients; 25 (61.0%) were squamous cell carcinomas, 12 (29.3%) were adenocarcinomas, 2 (4.9%) were adenosquamous cell carcinomas, and 2 (4.9%) were neuroendocrine tumors. Thirty-nine of 65 patients (60.0%) had HPV-16-positive tumors and 21 patients (32.3%) had HPV-18-positive tumors. In the analysis of cross-reactivity, 1 of 16 oncoprotein-reactive archived TILs (9 from cervical cancers and 7 from other cancers) displayed HPV-16/HPV-18 cross-reactivity. None of the 10 oncoprotein-reactive TCRs displayed HPV-16/HPV-18 cross-reactivity. Conclusions and Relevance:Cervical cancers that tested positive for HPV-18 were common in this study and may be common in other US clinical trial populations. Results showed that HPV-16/HPV-18 intergenotype T-cell cross-reactivity of T cells from HPV-16-positive and HPV-18-positive cancers was uncommon. These findings support clinical trial designs in which the HPV type targeted by a therapeutic vaccine is matched with the HPV type of a cancer and suggest a change is necessary in the design of active clinical trials.
| S-EPMC6324313 | biostudies-other
Project description:ObjectivesThis study used longitudinal, narrative data to identify trajectories of recovery among homeless adults with mental illness alongside the factors that contribute to positive, negative, mixed or neutral trajectories over time. We expected that participants who received Housing First (HF) would describe more positive trajectories of recovery than those who were assigned to Treatment as Usual (TAU; no housing or support provided through the study).DesignNarrative interview data were collected from participants at baseline and 18 months after random assignment to HF or TAU.SettingParticipants were sampled from the community in Vancouver, British Columbia.ParticipantsFifty-four participants were randomly and purposively selected from the larger trial; 52 were interviewed at baseline and 43 were reinterviewed 18 months after randomisation.MethodSemistructured interviews were conducted at both time points. For each participant, paired baseline and follow-up narratives were classified as positive, negative, mixed or neutral trajectories of recovery, and thematic analysis was used to identify the factors underlying different trajectories.ResultsParticipants assigned to HF (n=28) were generally classified as positive or mixed trajectories; those assigned to TAU (n=15) were generally classified as neutral or negative trajectories. Positive trajectories were characterised by a range of benefits associated with good-quality, stable housing (eg, reduced substance use, greater social support), positive expressions of identity and the willingness to self-reflect. Negative, neutral and mixed trajectories were characterised by hopelessness ('things will never get better') related to continued hardship (eg, eviction, substance use problems), perceived failures and loss.ConclusionsHF is associated with positive trajectories of recovery among homeless adults with mental illness. Those who did not receive housing or support continued to struggle across a wide range of life domains. Findings are discussed with implications for addressing services and broader social change in order to benefit this marginalised population.
| S-EPMC3773649 | biostudies-literature
Project description:BackgroundCopy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome.MethodsCopy number subtype frequency was established for 4 glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and the German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multi-institutional cohort focused on paired resected initial/recurrent glioblastoma. The paired initial/recurrent cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis.ResultsSmaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome.ConclusionsThe overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection toward longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population.
| S-EPMC6120353 | biostudies-literature
Project description:INTRODUCTION:The number of inconclusive physical rehabilitation randomised controlled trials for patients with critical illness is increasing. Evidence suggests critical illness patient subgroups may exist that benefit from targeted physical rehabilitation interventions that could improve their recovery trajectory. We aim to identify critical illness patient subgroups that respond to physical rehabilitation and map recovery trajectories according to physical function and quality of life outcomes. Additionally, the utilisation of healthcare resources will be examined for subgroups identified. METHODS AND ANALYSIS:This is an individual participant data meta-analysis protocol. A systematic literature review was conducted for randomised controlled trials that delivered additional physical rehabilitation for patients with critical illness during their acute hospital stay, assessed chronic disease burden, with a minimum follow-up period of 3?months measuring performance-based physical function and health-related quality of life outcomes. From 2178 records retrieved in the systematic literature review, four eligible trials were identified by two independent reviewers. Principal investigators of eligible trials were invited to contribute their data to this individual participant data meta-analysis. Risk of bias will be assessed (Cochrane risk of bias tool for randomised trials). Participant and trial characteristics, interventions and outcomes data of included studies will be summarised. Meta-analyses will entail a one-stage model, which will account for the heterogeneity across and the clustering between studies. Multiple imputation using chained equations will be used to account for the missing data. ETHICS AND DISSEMINATION:This individual participant data meta-analysis does not require ethical review as anonymised participant data will be used and no new data collected. Additionally, eligible trials were granted approval by institutional review boards or research ethics committees and informed consent was provided for participants. Data sharing agreements are in place permitting contribution of data. The study findings will be disseminated at conferences and through peer-reviewed publications. PROSPERO REGISTRATION NUMBER:CRD42019152526.
| S-EPMC7223158 | biostudies-literature
Project description:Background & aimsThe predicted risk and timeline to progression to liver-related outcomes in the population with NAFLD are not well-characterized. We aimed to examine the risk and time to progression to cirrhosis, hepatic decompensation and death in a contemporary population over a long follow-up period, to obtain information to guide endpoint selection and sample size calculations for clinical trials on NAFLD-related cirrhosis.MethodsThis is a retrospective study of prospectively collected data in a medical record linkage system, including all adults diagnosed with NAFLD between 1996-2016 by clinical, biochemical and radiological criteria in Olmsted County, Minnesota and followed until 2019. Liver-related outcomes and death were ascertained and validated by individual medical record review. Time and risk of progression from NAFLD to cirrhosis to decompensation and death were assessed using multistate modeling.ResultsA total of 5,123 individuals with NAFLD (median age 52 years, 53% women) were followed for a median of 6.4 (range 1-23) years. The risk of progression was as follows: from NAFLD to cirrhosis: 3% in 15 years; compensated cirrhosis to first decompensation: 33% in 4 years (8%/year); first decompensation to ≥2 decompensations: 48% in 2 years. Albumin, bilirubin, non-bleeding esophageal varices and diabetes were independent predictors of decompensation. Among the 575 deaths, 6% were liver related. Therapeutic trials in compensated cirrhosis would require enrolment of a minimum of 2,886 individuals followed for >2 years to detect at least a 15% relative decrease in liver-related endpoints.ConclusionIn this population-based cohort with 23 years of longitudinal follow-up, NAFLD was slowly progressive, with liver-related outcomes affecting only a small proportion of people. Large sample sizes and long follow-up are required to detect reductions in liver-related endpoints in clinical trials.Lay summaryFor patients with compensated non-alcoholic steatohepatitis-related cirrhosis, the time spent in this state and the risk of progression to decompensation are not well-known in the population. We examined the clinical course of a large population-based cohort over 23 years of follow-up. We identified that adults with compensated cirrhosis spend a mean time of 4 years in this state and have a 10% per year risk of progression to decompensation or death. The risk of further progression is 3-fold higher in adults with cirrhosis and one decompensating event. These results are reflective of placebo arm risks in drug clinical trials and are essential in the estimation of adequate sample sizes.
| S-EPMC9974107 | biostudies-literature