Initiation of symptomatic medication in Alzheimer's disease clinical trials: Hypothetical versus treatment policy approach.
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ABSTRACT:
SUBMITTER: Donohue MC
PROVIDER: S-EPMC8317593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeIntracranial atherosclerosis is especially prevalent in Asians, but intracranial stent placement and medical treatment for severe intracranial stenosis are controversial. Thus, we compared long-term outcomes of these 2 therapeutic approaches in an Asian population.Materials and methodsPatients with angiographically proved severe (≥70%) symptomatic intracranial atherosclerosis, with or without stent placement, were retrospectively reviewed at a single center between 2002 and 2009, with adjustments for age, sex, vascular risk factors, degree of baseline stenosis, and baseline functional status.ResultsOf the 114 patients followed from 3 to 36 months (mean, 17.3 months) after initial diagnosis, 53 received 56 stents in addition to medical treatment (stent-placement group), and 61 matched patients received only medical treatment (medical group). Total clinical events, including stroke, TIA, and vascular death, were 12 (22.6%) and 15 (24.6%) in the stent-placement and medical groups, respectively (P = .99). The stent-placement group had significantly better functional outcomes than the medical group (94.3% versus 78.7% for mRS scores of 0-3, P = .045). Most events in the stent-placement group occurred within the first week of the periprocedural period (17.0%) as minor embolic or perforator infarctions, and the rate of events decreased thereafter (5.7%, P = .07). Stent placement over the perforator-rich MCA and BA independently predicted periprocedural events on multivariate regression analysis. In the medical group, events increased in frequency (21.7%) and severity with time.ConclusionsAlthough the total ischemic event rate was similar in the 2 groups during a 3-year follow-up, the stent-placement group had a more favorable functional outcome despite minor periprocedural strokes.
| S-EPMC7965542 | biostudies-literature
Project description:BackgroundThe effectiveness of operative compared with nonoperative treatment at initial presentation (no prior fusion) for adult lumbar scoliosis has not, to our knowledge, been evaluated in controlled trials. The goals of this study were to evaluate the effects of operative and nonoperative treatment and to assess the benefits of these treatments to help treating physicians determine whether patients are better managed operatively or nonoperatively.MethodsPatients with adult symptomatic lumbar scoliosis (aged 40 to 80 years, with a coronal Cobb angle measurement of ≥30° and an Oswestry Disability Index [ODI] score of ≥20 or Scoliosis Research Society [SRS]-22 score of ≤4.0) from 9 North American centers were enrolled in concurrent randomized or observational cohorts to evaluate operative versus nonoperative treatment. The primary outcomes were differences in the mean change from baseline in the SRS-22 subscore and ODI at 2-year follow-up. For the randomized cohort, the initial sample-size calculation estimated that 41 patients per group (82 total) would provide 80% power with alpha equal to 0.05, anticipating 10% loss to follow-up and 20% nonadherence in the nonoperative arm. However, an interim sample-size calculation estimated that 18 patients per group would be sufficient.ResultsSixty-three patients were enrolled in the randomized cohort: 30 in the operative group and 33 in the nonoperative group. Two hundred and twenty-three patients were enrolled in the observational cohort: 112 in the operative group and 111 in the nonoperative group. The intention-to-treat analysis of the randomized cohort found that, at 2 years of follow-up, outcomes did not differ between the groups. Nonadherence was high in the randomized cohort (64% nonoperative-to-operative crossover). In the as-treated analysis of the randomized cohort, operative treatment was associated with greater improvement at the 2-year follow-up in the SRS-22 subscore (adjusted mean difference, 0.7 [95% confidence interval (CI), 0.5 to 1.0]) and in the ODI (adjusted mean difference, -16 [95% CI, -22 to -10]) (p < 0.001 for both). Surgery was also superior to nonoperative care in the observational cohort at 2 years after treatment on the basis of SRS-22 subscore and ODI outcomes (p < 0.001). In an overall responder analysis, more operative patients achieved improvement meeting or exceeding the minimal clinically important difference (MCID) in the SRS-22 subscore (85.7% versus 38.7%; p < 0.001) and the ODI (77.4% versus 38.3%; p < 0.001). Thirty-four revision surgeries were performed in 24 (14%) of the operative patients.ConclusionsOn the basis of as-treated and MCID analyses, if a patient with adult symptomatic lumbar scoliosis is satisfied with current spine-related health, nonoperative treatment is advised, with the understanding that improvement is unlikely. If a patient is not satisfied with current spine health and expects improvement, surgery is preferred.Level of evidenceTherapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
| S-EPMC6738555 | biostudies-literature
Project description:BackgroundThe use of surrogate and composite endpoints, disease-specific mortality as an endpoint, and relative (rather than absolute) risk reporting in clinical trials may produce results that are misleading or difficult to interpret.ObjectiveTo describe the prevalence of these endpoints and of relative risk reporting in medication trials. DESIGN AND MAIN MEASURES: We analyzed all randomized medication trials published in the six highest impact general medicine journals between June 1, 2008 and September 30, 2010 and determined the percentage using these endpoints and the percentage reporting results in the abstract exclusively in relative terms.Key resultsWe identified 316 medication trials, of which 116 (37%) used a surrogate primary endpoint and 106 (34%) used a composite primary endpoint. Among 118 trials in which the primary endpoint involved mortality, 32 (27%) used disease-specific mortality rather than all-cause mortality. Among 157 trials with positive results, 69 (44%) reported these results in the abstract exclusively in relative terms. Trials using surrogate endpoints and disease-specific mortality as an endpoint were more likely to be exclusively commercially funded (45% vs. 29%, difference 15% [95% CI 5%-26%], P = 0.004, and 39% vs. 16%, difference 22% [95% CI 6%-37%], P = 0.007, respectively). Trials using surrogate endpoints were more likely to report positive results (66% vs. 49%, difference 17% [95% CI 5%-28%], P = 0.006) while those using mortality endpoints were less likely to be positive (46% vs. 62%, difference -16% [95% CI -27%--4%], P = 0.01).ConclusionsThe use of surrogate and composite endpoints, endpoints involving disease-specific mortality, and relative risk reporting is common. Articles should highlight the limitations of these endpoints and should report results in absolute terms.
| S-EPMC3208473 | biostudies-literature
Project description: Not available
| S-EPMC7437396 | biostudies-literature
Project description:BackgroundCurrent guidelines recommend empiric antibiotics as first-line treatment for uncomplicated UTI. Despite proven benefits in treatment, antibiotic resistance rates remain on the rise. This meta-analysis aims to determine whether non-steroidal anti-inflammatory drugs can serve as an effective and safe option in the treatment of uncomplicated lower UTI among non-pregnant women compared to antibiotics.MethodsA systematic literature search in PUBMED, CENTRAL, and ACP databases from inception to April 2021 was conducted to identify randomized controlled trials that compare the use of non-steroidal anti-inflammatory drugs versus antibiotics in non-pregnant women ≥18 years old with uncomplicated lower urinary tract infection. Primary outcomes were symptom resolution of UTI by Day 3 or 4 of intervention, and upper UTI complications. Secondary outcomes include persistence of positive urine culture despite treatment and need for another rescue antibiotic. Random and fixed-effects model for dichotomous data using Mantel-Haenszel and Peto odds method were reported at 95% CI followed by sensitivity analysis for substantial heterogeneity.ResultsFour RCTs involving 1165 patients were analyzed. The probability of having a symptom resolution by Day 3 or 4 with NSAID use is only less than three-fourths of that with antibiotic treatment (RR: 0.69, 95% CIs [0.55, 0.86], p = 0.0008, I2 = 73%, moderate certainty of evidence). The odds of developing upper UTI complications with use of NSAIDs are 6.49 to 1 for antibiotics (Peto OR: 6.49, 95% CIs [3.02, 13.92], p < 0.00001, I2 = 0%, moderate certainty of evidence). Secondary analysis showed that the NSAID group is 2.77x more likely to have persistence of a positive microbiologic urine culture than the antibiotic group (RR: 2.77, 95% CIs [1.95, 3.94], p < 0.00001, I2 = 36%, moderate certainty of evidence). Treatment with NSAIDs are three times more likely to use a secondary or rescue antibiotic due to persistent or worsening symptoms as compared to antibiotics (RR: 3.16, 95% CIs [2.24, 4.44], p < 0.00001, I2 = 47%, low certainty of evidence).ConclusionAntibiotic treatment was more effective than use of non-steroidal anti-inflammatory drugs for acute uncomplicated lower urinary tract infection with an overall moderate certainty of evidence.
| S-EPMC8243445 | biostudies-literature
Project description:BackgroundNon-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials.MethodsThe frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis.ResultsThe two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million.ConclusionsThis study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.
| S-EPMC4468148 | biostudies-literature
Project description:Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.
| S-EPMC5269514 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor showing a tendency for early recurrence, even after curative resection. Although adjuvant treatment improves survival, it is unclear whether early adjuvant treatment initiation yields better outcomes in patients with PDAC.MethodsWe retrospectively enrolled 113 patients who underwent chemotherapy or chemoradiotherapy after curative resection of PDAC: Fifty-six and 57 patients were in the early and delayed groups, respectively based on the median time of treatment initiation (35 days [range, 20-83 days]).ResultsPatient baseline characteristics were comparable in both groups, except for grade III or IV postoperative complications (5.4% in the early group vs. 22.8% in the delayed group). With a median 20.3-month follow-up, the overall survival (OS) and disease-free survival (DFS) times were 29.5 and 14.7 months, respectively. The early group had significantly prolonged OS (39.1 vs. 21.1 months, p = 0.018) and DFS (18.8 vs. 10.0 months, p = 0.034), compared to the delayed group. Among 71 patients who completed planned adjuvant treatment, patients in the early group tended to have longer, though not statistically significant, OS and DFS times than those in the delayed group. In 67 patients without postoperative complications, patients in the early group had longer OS (42.8 vs. 20.5 months, p = 0.002) and DFS (19.6 vs. 9.1 months, p = 0.005) than those in the delayed group. By multivariate analysis, incompletion of treatment (hazard ratio [HR]: 4.039, 95% confidence interval [CI]: 2.334-6.992), delayed treatment initiation (HR: 1.822, 95% CI: 1.081-3.070), and positive angiolymphatic invasion (HR: 2.116, 95% CI: 1.160-3.862) were significantly associated with shorter OS.ConclusionsAdjuvant treatment should be delivered earlier and completed for better outcomes in resected PDAC patients, especially without postoperative complications.
| S-EPMC5354454 | biostudies-literature
Project description:IntroductionThere is increasing emphasis on the importance of optimizing and standardizing clinical trials of agitation in Alzheimer's disease (AD), but the risks of bias arising from published trials and the number and design of unpublished studies are poorly understood.MethodsUsing the ClinicalTrials.gov database, we systematically reviewed all registered investigational clinical trials for agitation in AD to describe the landscape of agitation drug treatment trials and to assess their quality and generalizability.ResultsWe included 52 clinical studies registered over the past 25 years. Within published randomized controlled trials (RCTs), there was a high rate of participant dropout, poor reporting of randomization procedures, and inconsistent definitions of the sample included for analysis. There was also evidence of publication and funder bias.DiscussionWe discuss factors that limit the internal and external validity of published RCTs and make additional recommendations for the conduct and reporting of future clinical trials of agitation in AD.
| S-EPMC8010365 | biostudies-literature
Project description:Alterations of protein abundance and post-translational modifications in patients with Alzheimer’s disease (AD), such as glycosylation, phosphorylation, and ubiquitination, and their roles in disease progression and treatment outcome are areas of intense study. Little is known, however, about the overall N-glycosylation of proteins in human brains, and those from Alzheimer’s patients, particularly in regard to large-scale intact N-linked glycoproteomics analysis. To elucidate the glycoproteome landscape, we developed an approach based on multi-lectin affinity enrichment, hydrophilic interaction chromatography (HILIC), and LC-MS-based glycoproteomics analysis. We analyzed 10 normal, 10 asymptomatic, and 10 symptomatic AD brains, in which we detected >300 glycoproteins and >1,900 glycoforms across the samples. The majority of glycoproteins have N-glycans that are high-mannosidic and complex chains that are fucosylated and bisected. The Man5 N-glycan was found to occur most frequently at >20% of the total glycoforms. Unlike the glycoproteomes of other tissues, sialylation is a minor feature of the brain glycoproteome, occurring at <9% of N-glycans . We observed changes in the number of antennae, frequency of fucosylation, bisection, and other monosaccharides at individual glycosylation sites among normal, asymptomatic, and symptomatic AD samples. Further analysis revealed glycosylation differences in subcellular compartments. We did not observe a statistical difference between male and female patients. These results represent the first glycoproteomics landscape of brains from multiple AD individuals, which will facilitate a deeper understanding of AD and possible disease treatment options.
2022-10-31 | PXD032219 | Pride