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American Society of Clinical Oncology... Jun 2024Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past... (Review)
Review
Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.
Topics: Humans; Neoplasms; Clinical Trials as Topic; Research Design; Pragmatic Clinical Trials as Topic; Medical Oncology
PubMed: 38771997
DOI: 10.1200/EDBK_100040 -
Gynecologic Oncology Oct 2023Prior to the COVID-19 pandemic, telehealth visits and remote clinical trial operations (such as local collection of laboratory tests or imaging studies) were...
OBJECTIVE
Prior to the COVID-19 pandemic, telehealth visits and remote clinical trial operations (such as local collection of laboratory tests or imaging studies) were underutilized in gynecologic oncology clinical trials. Current literature on these operational changes provides anecdotal experience and expert opinion with few studies describing patient-level safety data. We aimed to evaluate the safety and feasibility of telehealth and remote clinical trial operations during the COVID-19 Pandemic.
METHODS
Gynecologic oncology patients enrolled and actively receiving treatment on a clinical trial at a single, academic institution during the designated pre-Telehealth and Telehealth periods were identified. Patients with at least 1 provider or research coordinator telehealth visit were included. Patient demographics, health system encounters, adverse events, and protocol deviations were collected. Pairwise comparisons were performed between the pre-Telehealth and Telehealth period with each patient serving as their own control.
RESULTS
Thirty-one patients met inclusion criteria. Virtual provider visits and off-site laboratory testing increased during the Telehealth period. Delays in provider visits, imaging, and laboratory testing did not differ between time periods. Total and minor protocol deviations increased in incidence during the Telehealth period and were due to documentation of telehealth and deferment of non-therapeutic testing. Major protocol deviations, emergency department visits, admissions, and severe adverse events were of low incidence and did not differ between time periods.
CONCLUSIONS
Telehealth and remote clinical trial operations appeared safe and did not compromise clinical trial protocols in a small, single institutional study. Larger scale evaluations of such trial adaptations should be performed to determine continued utility following the Pandemic.
PubMed: 37659265
DOI: 10.1016/j.ygyno.2023.08.011 -
Journal of Diabetes and Its... Aug 2023Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been verified to improve Non-alcoholic fatty liver disease (NAFLD) in previous clinical practice. We mainly aim... (Meta-Analysis)
Meta-Analysis
Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: An updated meta-analysis of randomized controlled trials.
BACKGROUND AND AIM
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been verified to improve Non-alcoholic fatty liver disease (NAFLD) in previous clinical practice. We mainly aim to investigate the effects of SGLT2i on liver fibrosis in NAFLD patients with type 2 diabetes mellitus (T2DM).
METHODS
We conducted a comprehensive literature search utilizing the databases PubMed, Embase, Web of Science, and Cochrane Library, and extracted continuous data in the form of mean and standard deviation of the difference before and after treatment. RevMan 5.3 software was used to chart the pooled forest plot and perform heterogeneity, sensitivity and subgroup analysis. This study is conducted under the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY protocol 4946, INPLASY202360058).
RESULTS
A total of 16 articles involving 699 patients were included. Indicators of liver fibrosis, containing Liver Stiffness Measurement (LSM), Controlled Attenuation Parameter (CAP), Serum ferritin, Serum type 4 collagen 7s, and FIB-4 index, were found to be considerably reduced by SGLT2i medication and subgroup analysis manifested pronounced dose-dependence. Additionally, SGLT2i therapy decreased BMI, lipid buildup and insulin resistance.
CONCLUSIONS
SGLT2 inhibitors significantly ameliorated liver fibrosis and liver fat content, improved body conditions and insulin resistance, demonstrating that SGLT2i might reduce the risk of the progression of liver fibrosis and have a positive effect on NAFLD patients with T2DM.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Resistance; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37499274
DOI: 10.1016/j.jdiacomp.2023.108558 -
The International Journal of Lower... Feb 2024Randomized controlled trials represent the cornerstone for the regulatory approval of drugs and evidence-based medicine and policy. Compared with observational studies... (Review)
Review
Randomized controlled trials represent the cornerstone for the regulatory approval of drugs and evidence-based medicine and policy. Compared with observational studies random assignment of participants to each study arm guarantees an equal distribution of potential confounders thus achieving impartiality in the evaluation of between group differences and allowing for causal inferences to be drawn. These complex and costly medical experiments are tightly regulated and require substantial planning with great attention to several methodological aspects ranging from allocation concealment and blinding to sample size estimation, statistical analysis, and handling of protocol deviations. This brief guide offers useful insights into the design, conduct, and interpretation of clinical trial findings for beginners.
PubMed: 38419478
DOI: 10.1177/15347346241236385 -
Journal of Vascular Surgery Dec 2023Systematic reviews (SRs) and meta-analyses are essential in informing clinical guidelines and decision-making. Complete reporting of SRs through compliance to the... (Review)
Review
OBJECTIVE
Systematic reviews (SRs) and meta-analyses are essential in informing clinical guidelines and decision-making. Complete reporting of SRs through compliance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines promotes transparency, reproducibility, and consistency across the literature. The purpose of this meta-epidemiological study is to assess the completeness of reporting of SRs in the vascular surgery literature.
METHODS
MEDLINE and Embase were used to search through four major vascular surgery journals and four high impact general medical journals for SRs published between 2018 and October 2022 evaluating clinical treatments for any pathology treated by a vascular surgeon. Data screening and extraction were conducted in duplicate. The reporting completeness of each included SR was measured with reference to the 27-item PRISMA checklist, and methodological quality was evaluated using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) tool. Parametric tests were used to evaluate for associations between PRISMA score and study funding, protocol registration, publication in a higher impact factor journal, and AMSTAR 2 score. The protocol is available online: 10.17605/OSF.IO/VBC5N.
RESULTS
Of 1653 articles captured in the initial search, 162 SRs were included in the final analysis. All SRs had more than one incomplete PRISMA item. The mean PRISMA score was 21.2/27 (standard deviation: 2.9, 78.5% compliance), and the mean AMSTAR 2 score was 11.7/16 (standard deviation: 1.9, 73%). SRs that had a prospectively registered protocol had a higher PRISMA score (22.9 vs 20.6, P < .001) as did those that were published in higher impact factor journals (23.3 vs 21.0, P = .017). There was a large positive correlation between an SR's PRISMA and AMSTAR 2 scores (Pearson r = 0.655, 95% confidence interval: 0.55-0.74). There were no associations between the PRISMA score and publication year (P = .067) or funding status (P = .076).
CONCLUSIONS
Overall, the reporting of SRs and meta-analyses in vascular surgery is less than ideal, with several key items being consistently under-reported. Prospective registration and methodological quality as measured by AMSTAR 2 scores are positively associated with improved reporting. Authors, reviewers, and journal editors should consider these findings moving forward to encourage completeness of SR reporting. Raising awareness surrounding the value of complete reporting of SRs can aid in enhancing the quality of evidence, and journals should consider these findings in methods used to promote SR reporting.
Topics: Humans; Prospective Studies; Reproducibility of Results; Vascular Surgical Procedures; Specialties, Surgical; Surgeons
PubMed: 37068527
DOI: 10.1016/j.jvs.2023.04.009 -
JAMA Neurology Dec 2023Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence.
OBJECTIVE
To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale.
DESIGN, SETTING, AND PARTICIPANTS
Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause.
INTERVENTIONS
Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day.
MAIN OUTCOMES AND MEASURES
IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other.
RESULTS
A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority.
CONCLUSION AND RELEVANCE
Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02878798.
Topics: Aged; Female; Humans; Male; Middle Aged; Diabetic Neuropathies; Double-Blind Method; Metabolic Syndrome; Neuralgia; Quality of Life; Topiramate; Adolescent; Young Adult; Adult; Aged, 80 and over
PubMed: 37870862
DOI: 10.1001/jamaneurol.2023.3711 -
Journal of Bioethical Inquiry Sep 2023Uterus transplantation (UTx) research has been introduced in several countries, with trials in Sweden and the United States producing successful outcomes. The growing...
Uterus transplantation (UTx) research has been introduced in several countries, with trials in Sweden and the United States producing successful outcomes. The growing interest in developing UTx trials in other countries, such as Spain, the Netherlands, Japan, and Australia, raises important questions regarding the ethics of surgical innovation research in the field of UTx. This paper examines the current state of UTx in the context of the surgical innovation paradigm and IDEAL framework and discusses the ethical challenges faced by those considering the introduction of new trials. We argue that UTx remains an experimental procedure at a relatively early stage of the IDEAL framework, especially in the context of de novo trials, where protocols are likely to deviate from those used previously and where researchers are likely to have limited experience of UTx. We conclude that countries considering the introduction of UTx trials should build on the strengths of the reported outcomes to consolidate the evidence base and shed light on the uncertainties of the procedure. Authorities responsible for the ethical governance of UTx trials are advised to draw on the ethical framework used in the oversight of surgical innovation.
Topics: Female; Humans; Infertility, Female; Organ Transplantation; Uterus; Japan; Sweden
PubMed: 37382845
DOI: 10.1007/s11673-023-10272-5 -
Journal of Neuro-ophthalmology : the... Dec 2023Evaluating patients with potentially sight-threatening conditions frequently involves urgent neuroimaging, and some providers recommend expediting emergency department...
BACKGROUND
Evaluating patients with potentially sight-threatening conditions frequently involves urgent neuroimaging, and some providers recommend expediting emergency department (ED) evaluation. However, several factors may limit the practicality of ED evaluation. This pilot study assessed the feasibility and safety of a STAT magnetic resonance imaging (MRI) protocol, designed to facilitate outpatient MRI within 48 hours of referral, compared with ED evaluation for patients with optic disc edema.
METHODS
A retrospective chart review was performed. Demographics, clinical data, and baseline ophthalmic measures were compared between patients in STAT and ED groups using the t test or Fisher exact test. Multivariate analyses compared changes in visual acuity (VA), visual field mean deviation (VF MD), retinal nerve fiber layer thickness, and edema grade between presentation and follow-up using a mixed-effects model adjusting for age, sex, and baseline measures.
RESULTS
A total of 70 patients met the study criteria-24 (34.3%) in the STAT MRI cohort and 46 (65.7%) in the ED cohort. Demographic variables were similar between groups. Patients referred to the ED had worse VA ( P < 0.001), larger VF MD ( P < 0.001), and higher edema grade ( P = 0.002) at presentation. Four patients in the ED group and none in the STAT group were found to have space-occupying lesions. Multivariate analyses showed that follow-up measures were significantly associated with their baseline values (all P < 0.001) but not with referral protocol (all P > 0.099). The STAT MRI protocol was associated with lower average patient charges and hospital costs.
CONCLUSIONS
The STAT MRI protocol did not result in inferior visual outcomes or delay in life-threatening diagnoses. Urgent outpatient evaluation, rather than ED referral, seems safe for some patients with optic disc edema. These findings support continued utilization of the protocol and ongoing improvement efforts.
PubMed: 38051953
DOI: 10.1097/WNO.0000000000002053 -
JTCVS Techniques Aug 2023To develop a minimally invasive, reproducible model of chronic severe mitral regurgitation (MR) that replicates the clinical phenotype of left atrial (LA) and left...
OBJECTIVE
To develop a minimally invasive, reproducible model of chronic severe mitral regurgitation (MR) that replicates the clinical phenotype of left atrial (LA) and left ventricular dilation and susceptibility to atrial fibrillation.
METHODS
Under transesophageal echocardiographic guidance, chordae tendinae were avulsed using endovascular forceps until the ratio of regurgitant jet area to LA area was ≥70%. Animals survived for an average of 8.6 ± 1.6 months (standard deviation) and imaged with monthly transthoracic echocardiography (TTE). Animals underwent baseline and preterminal magnetic resonance imaging. Terminal studies included TTE, transesophageal echocardiography, and rapid atrial pacing to test inducibility of atrial tachyarrhythmias.
RESULTS
Eight dogs underwent creation of severe MR and interval monitoring. Two were excluded-one died from acute heart failure, and the other had resolution of MR. Six dogs underwent the full experimental protocol; only one required medical management of clinical heart failure. MR remained severe over time, with a mean terminal regurgitant jet area to LA area of 71 ± 14% (standard deviation) and regurgitant fraction of 52 ± 11%. Mean LA volume increased over 130% (TTE: 163 ± 147%, = .039; magnetic resonance imaging: 132 ± 54%, = .011). Mean left ventricular end-diastolic volume increased by 38 ± 21% ( = .008). Inducible atrial tachyarrhythmias were seen in 4 of 6 animals at terminal surgery, and none at baseline.
CONCLUSIONS
Within the 6 dogs that successfully completed the full experimental protocol, this model replicated the clinical phenotype of severe MR, which led to marked structural and electrophysiologic cardiac remodeling. This model allowed for precise measurements at repeated time points and will facilitate future studies to elucidate the mechanisms of atrial and ventricular remodeling secondary to MR and the pathophysiology of valvular atrial fibrillation.
PubMed: 37555041
DOI: 10.1016/j.xjtc.2023.03.027 -
Journal of Sports Science & Medicine Dec 2023The onset of fatigue disrupts the functioning of the autonomic nervous system (ANS), potentially elevating the risk of life-threatening incidents and impairing daily...
The onset of fatigue disrupts the functioning of the autonomic nervous system (ANS), potentially elevating the risk of life-threatening incidents and impairing daily performance. Previous studies mainly focused on physical fatigue (PF) and mental fatigue (MF) effects on the ANS, with limited knowledge concerning the influence of physical-mental fatigue (PMF) on ANS functionality. This study aimed to assess the immediate impact of PMF on ANS function and to compare its effects with those of PF and MF on ANS function. Thirty-six physically active college students (17 females) without burnout performed 60-min cycling exercises, AX-Continuous Performance Task (AX-CPT), and cycling combined with AX-CPT to induce PF, MF, and PMF respectively. Subjective fatigue levels were measured using the Rating of Perceived Exertion scale and the Visual Analog Scale-Fatigue. Heart rate variability was measured before and after each protocol to assess cardiac autonomic function. The proposed tasks successfully induced PF, MF, and PMF, demonstrated by significant changes in subjective fatigue levels. Compared with baseline, PMF decreased the root mean square of successive differences (RMSSD) between normal heartbeats ( < 0.001, = 0.50), the standard deviation of normal-to-normal RR intervals (SDNN) ( < 0.01, = 0.33), and the normalized high-frequency (nHF) power ( < 0.001, = 0.32) while increased the normalized low-frequency (nLF) power ( < 0.001, = 0.35) and the nLF/nHF ratio ( < 0.001, = 0.40). Compared with MF, PMF significantly decreased RMSSD ( < 0.001, η = 0.431), SDNN ( < 0.001, η = 0.327), nLF ( < 0.01, η = 0.201), and nHF ( < 0.001, η = 0.377) but not the nLF/nHF ratio. There were no significant differences in ΔHRV (i.e., ΔRMSSD, ΔSDNN, ΔnLF/nHF, ΔnLF, and ΔnHF), heart rate, and training impulse between PF- and PMF-inducing protocols. Cognitive performance (i.e., accuracy) in AX-CPT during the PMF-inducing protocol was significantly lower than that during the MF-inducing protocol ( < 0.001, η = 0.101). PF and PMF increased sympathetic activity and decreased parasympathetic activity, while MF enhanced parasympathetic activity.
Topics: Female; Humans; Autonomic Nervous System; Exercise; Exercise Therapy; Mental Fatigue
PubMed: 38045744
DOI: 10.52082/jssm.2023.806