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1.
A Real-World Observational Cohort of Patients with Hepatocellular Carcinoma: Design and Rationale for TARGET-HCC.
Cabrera, R, Singal, AG, Colombo, M, Kelley, RK, Lee, H, Mospan, AR, Meyer, T, Newell, P, Parikh, ND, Sangro, B, et al
Hepatology communications. 2021;(3):538-547
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Abstract
This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient-reported outcome measures and provide biological specimens for future translational studies. The TARGET-HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol-related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET-HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.
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The use of 3D ultrasound in comparing surgical techniques for posterior wall prolapse repair: a pilot randomised controlled trial.
Derpapas, A, Vijaya, G, Nikolopoulos, K, Nikolopoulos, M, Robinson, D, Fernando, R, Khullar, V
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2021;(4):594-600
Abstract
The most appropriate method for repairing posterior vaginal wall prolapse is still debatable. Women with symptomatic prolapse scheduled to undergo surgical repair in the posterior compartment were randomised to standard posterior colporrhaphy (SPC) or fascial and vaginal epithelial plication (FEP). Participants were assessed with the Prolapse Quality of Life (P-QOL) questionnaire, pelvic organ prolapse quantification (POP-Q) examination and three-dimensional ultrasound (3D US) prior to surgery and 6 months postoperatively. The research hypothesis is that 3D US of the pelvic floor is a reliable tool in comparing the anatomical outcomes of the two different surgical techniques. Differences in anatomical outcomes, assessed clinically and by ultrasonographic evaluation, were compared between the two groups using the Independent Mann-Whitney U-test and the Wilcoxon signed-rank sum test. Twenty-two women were included in the analysis. Six months postoperatively, women in the FEP arm had better anatomical outcomes compared to those who had undergone SPC (p = .02). Repeatability of the ultrasound technique was confirmed, showing moderate to very good agreement in all parameters and the 3D US evaluation was corroborated with the clinical examination, showing a greater reduction in the urogenital size in the FEP group.Impact statementWhat is already known on this subject? The low cost and universal availability of the ultrasound (US) makes it the most commonly used diagnostic modality. The ability to see beyond surface anatomy is important and useful in the assessment of the posterior vaginal wall prolapse and the obstructed defaecation, where this method may replace the defaecation proctography (Dietz 2019). Recent advances in pelvic floor ultrasonography (3D US) have achieved repeatability in the measurement of the levator hiatal (LH) dimensions, introducing a valid and readily available tool for researchers and clinicians (Dietz et al. 2005). Ultrasound may distinguish a true rectocele due to the weakening of the rectovaginal fascia from an enterocele, a rectal intussusception, or just a deficient perineum (Guzman Rojas et al. 2016).What do the results of this study add? Our study demonstrates that 3D translabial pelvic floor ultrasound is a useful and reliable tool in assessing the anatomical outcome of prolapse surgery.What are the implications of these findings for clinical practice and/or further research? Our study demonstrates that 3D translabial ultrasound of the pelvic floor is a useful and reproducible method in evaluating the anatomical outcomes of surgical repair for posterior wall prolapse. Genital hiatus (GH) and levator hiatus (LH) dimensions measured by ultrasound can be used as surrogate anatomical markers in comparing the efficacy of different surgical techniques.
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Systematic Review of Outcome Measures Used in Observational Studies of Adults with Eosinophilic Esophagitis.
Schoepfer, AM, Schürmann, C, Trelle, S, Zwahlen, M, Ma, C, Chehade, M, Dellon, ES, Jairath, V, Feagan, BG, Bredenoord, AJ, et al
International archives of allergy and immunology. 2021;(12):1169-1193
Abstract
BACKGROUND Over the last 20 years, diverse outcome measures have been used to evaluate the effectiveness of therapies for eosinophilic esophagitis (EoE). This systematic review aims to identify the readouts used in observational studies of topical corticosteroids, diet, and dilation in adult EoE patients. METHODS We searched MEDLINE and Embase for prospective and retrospective studies (cohorts/case series, randomized open-label, and case-control) evaluating the use of diets, dilation, and topical corticosteroids in adults with EoE. Two authors independently assessed the articles and extracted information about histologic, endoscopic, and patient-reported outcomes and tools used to assess treatment effects. RESULTS We included 69 studies that met inclusion criteria. EoE-associated endoscopic findings (assessed either as absence/presence or using Endoscopic Reference Score) were evaluated in 24/35, 11/17, and 9/17 studies of topical corticosteroids, diet, and dilation, respectively. Esophageal eosinophil density was recorded in 32/35, 17/17, and 11/17 studies of topical corticosteroids, diet, and dilation, respectively. Patient-reported outcomes were not uniformly used (only in 14, 8, and 3 studies of topical corticosteroids, diet, and dilation, respectively), and most tools were not validated for use in adults with EoE. CONCLUSIONS Despite the lack of an agreed set of core outcomes that should be recorded and reported in studies in adult EoE patients, endoscopic EoE-associated findings and esophageal eosinophil density are commonly used to assess disease activity in observational studies. Standardization of outcomes and data supporting the use of outcomes are needed to facilitate interpretation of evidence, its synthesis, and comparisons of interventions in meta-analyses of therapeutic trials in adults with EoE.
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Short Physical Performance Battery: Response to Pulmonary Rehabilitation and Minimal Important Difference Estimates in Patients With Chronic Obstructive Pulmonary Disease.
Stoffels, AA, De Brandt, J, Meys, R, van Hees, HW, Vaes, AW, Klijn, P, Burtin, C, Franssen, FM, van den Borst, B, Sillen, MJ, et al
Archives of physical medicine and rehabilitation. 2021;(12):2377-2384.e5
Abstract
OBJECTIVE To determine the response to a pulmonary rehabilitation (PR) program and minimal important differences (MIDs) for the Short Physical Performance Battery (SPPB) subtests and SPPB summary score in patients with chronic obstructive pulmonary disease (COPD). DESIGN Retrospective analysis using distribution- and anchor-based methods. SETTING PR center in the Netherlands including a comprehensive 40-session 8-week inpatient or 14-week outpatient program. PARTICIPANTS A total of 632 patients with COPD (age, 65±8y; 50% male; forced expiratory volume in the first second=43% [interquartile range, 30%-60%] predicted). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Baseline and post-PR results of the SPPB, consisting of 3 balance standing tests, 4-meter gait speed (4MGS), and 5-repetition sit-to-stand (5STS). The chosen anchors were the 6-Minute Walk Test and COPD Assessment Test. Patients were stratified according to their SPPB summary scores into low-performance, moderate-performance, and high-performance groups. RESULTS 5STS (∆=-1.14 [-4.20 to -0.93]s) and SPPB summary score (∆=1 [0-2] points) improved after PR in patients with COPD. In patients with a low performance at baseline, balance tandem and 4MGS significantly increased as well. Based on distribution-based calculations, the MID estimates ranged between 2.19 and 6.33 seconds for 5STS and 0.83 to 0.96 points for SPPB summary score. CONCLUSIONS The 5STS and SPPB summary score are both responsive to PR in patients with COPD. The balance tandem test and 4MGS are only responsive to PR in patients with COPD with a low performance at baseline. Based on distribution-based calculations, an MID estimate of 1 point for the SPPB summary score is recommended in patients with COPD. Future research is needed to confirm MID estimates for SPPB in different centers.
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A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study.
Kgosidialwa, O, Bogdanet, D, Egan, AM, O'Shea, PM, Newman, C, Griffin, TP, McDonagh, C, O'Shea, C, Carmody, L, Cooray, SD, et al
BJOG : an international journal of obstetrics and gynaecology. 2021;(11):1855-1868
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Abstract
OBJECTIVE To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). DESIGN A consensus developmental study. SETTING International. POPULATION Two hundred and five stakeholders completed the first round. METHODS The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three-round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. MAIN OUTCOME MEASURES All outcomes were extracted from the literature. RESULTS We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester-specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy-induced hypertension, pre-eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. CONCLUSIONS This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. TWEETABLE ABSTRACT 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.
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Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet.
Noakes, TD
Open heart. 2021;(2)
Abstract
The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.
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Impact of discordance between patient's and evaluator's global assessment on treatment outcomes in 14 868 patients with spondyloarthritis.
Michelsen, B, Ørnbjerg, LM, Kvien, TK, Pavelka, K, Nissen, MJ, Nordström, D, Santos, MJ, Koca, SS, Askling, J, Rotar, Z, et al
Rheumatology (Oxford, England). 2020;(9):2455-2461
Abstract
OBJECTIVES To assess the impact of 'patient's minus evaluator's global assessment of disease activity' (ΔPEG) at treatment initiation on retention and remission rates of TNF inhibitors (TNFi) in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients across Europe. METHODS Real-life data from PsA and axSpA patients starting their first TNFi from 11 countries in the European Spondyloarthritis Research Collaboration Network were pooled. Retention rates were compared by Kaplan-Meier analyses with log-rank test and by Cox regression, and remission rates by χ2 test and by logistic regression across quartiles of baseline ΔPEG, separately in female and male PsA and axSpA patients. RESULTS We included 14 868 spondyloarthritis (5855 PsA, 9013 axSpA) patients. Baseline ΔPEG was negatively associated with 6/12/24-months' TNFi retention rates in female and male PsA and axSpA patients (P <0.001), with 6/12/24-months' BASDAI < 2 (P ≤0.002) and ASDAS < 1.3 (P ≤0.005) in axSpA patients, and with DAS28CRP(4)<2.6 (P ≤0.04) and DAPSA28 ≤ 4 (P ≤0.01), but not DAS28CRP(3)<2.6 (P ≥0.13) in PsA patients, with few exceptions on remission rates. Retention and remission rates were overall lower in female than male patients. CONCLUSION High baseline patient's compared with evaluator's global assessment was associated with lower 6/12/24-months' remission as well as retention rates of first TNFi in both PsA and axSpA patients. These results highlight the importance of discordance between patient's and evaluator's perspective on disease outcomes.
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Early score fluctuation and placebo response in a study of major depressive disorder.
Targum, SD, Cameron, BR, Ferreira, L, MacDonald, ID
Journal of psychiatric research. 2020;:118-125
Abstract
Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints. We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404. A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.
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Identifying Common Predictors of Multiple Adverse Outcomes Among Elderly Adults With Type-2 Diabetes.
Kabue, S, Liu, V, Dyer, W, Raebel, M, Nichols, G, Schmittdiel, J
Medical care. 2019;(9):702-709
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OBJECTIVE As part of a multidisciplinary team managing patients with type-2 diabetes, pharmacists need a consistent approach of identifying and prioritizing patients at highest risk of adverse outcomes. Our objective was to identify which predictors of adverse outcomes among type-2 diabetes patients were significant and common across 7 outcomes and whether these predictors improved the performance of risk prediction models. Identifying such predictors would allow pharmacists and other health care providers to prioritize their patient panels. RESEARCH DESIGN AND METHODS Our study population included 120,256 adults aged 65 years or older with type-2 diabetes from a large integrated health system. Through an observational retrospective cohort study design, we assessed which risk factors were associated with 7 adverse outcomes (hypoglycemia, hip fractures, syncope, emergency department visit or hospital admission, death, and 2 combined outcomes). We split (50:50) our study cohort into a test and training set. We used logistic regression to model outcomes in the test set and performed k-fold validation (k=5) of the combined outcome (without death) within the validation set. RESULTS The most significant predictors across the 7 outcomes were: age, number of medicines, prior history of outcome within the past 2 years, chronic kidney disease, depression, and retinopathy. Experiencing an adverse outcome within the prior 2 years was the strongest predictor of future adverse outcomes (odds ratio range: 4.15-7.42). The best performing models across all outcomes included: prior history of outcome, physiological characteristics, comorbidities and pharmacy-specific factors (c-statistic range: 0.71-0.80). CONCLUSIONS Pharmacists and other health care providers can use models with prior history of adverse event, number of medicines, chronic kidney disease, depression and retinopathy to prioritize interventions for elderly patients with type-2 diabetes.
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Generalizability of the FOURIER trial to routine clinical care: Do trial participants represent patients in everyday practice?
Yao, X, Gersh, BJ, Lopez-Jimenez, F, Shah, ND, Noseworthy, PA
American heart journal. 2019;:54-62
Abstract
BACKGROUND In the FOURIER trial, evolocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, reduced cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). We aimed to examine how closely patients in routine practice resemble the FOURIER trial participants and to assess the observed cardiovascular risks based on trial eligibility and underrepresentativeness. METHODS Using a large US administrative database with linked laboratory data, we identified adult patients with ASCVD between January 1, 2012, and December 31, 2016. We identified the excluded and underrepresented populations and examined the risk of cardiovascular events (a composite endpoint of myocardial infarction [MI], stroke, angina, and coronary revascularization) based on trial eligibility and underrepresentativeness. RESULTS Only 15.2% of 233,977 patients met the FOURIER eligibility. Nearly 60% of the ineligible patients met at least 2 exclusion criteria. Among trial-eligible patients, elderly patients, women, minorities, and those without prior MI were underrepresented in FOURIER. Patients who would have been excluded from FOURIER had a diverse risk profile but, on average, had a lower cardiovascular risk than those who would have qualified (hazard ratio [HR] 0.84 [0.81-0.88], P < .001). Among the underrepresented patients, women and patients without prior MI had a lower cardiovascular risk (HR 0.77 [0.71-0.82], P < .001; HR 0.67 [0.63-0.72], P < .001, respectively). Only 47.2% of patients were on moderate-/high-intensity statins. CONCLUSIONS One in 7 ASCVD patients in practice would have qualified for FOURIER. The excluded and underrepresented populations were at a particularly low or high cardiovascular risk. Statin therapy was underused, and physicians may need to evaluate adherence before adding a proprotein convertase subtilisin-kexin type 9 inhibitor.