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EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.
Kandimalla, R, Xu, J, Link, A, Matsuyama, T, Yamamura, K, Parker, MI, Uetake, H, Balaguer, F, Borazanci, E, Tsai, S, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(22):6135-6144
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Abstract
PURPOSE DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers. EXPERIMENTAL DESIGN Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panels RESULTS We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85-0.95 for most GI cancers. CONCLUSIONS Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.
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Using Caffeine Pills for Performance Enhancement. An Experimental Study on University Students' Willingness and Their Intention to Try Neuroenhancements.
Brand, R, Koch, H
Frontiers in psychology. 2016;:101
Abstract
Recent research has indicated that university students sometimes use caffeine pills for neuroenhancement (NE; non-medical use of psychoactive substances or technology to produce a subjective enhancement in psychological functioning and experience), especially during exam preparation. In our factorial survey experiment, we manipulated the evidence participants were given about the prevalence of NE amongst peers and measured the resulting effects on the psychological predictors included in the Prototype-Willingness Model of risk behavior. Two hundred and thirty-one university students were randomized to a high prevalence condition (read faked research results overstating usage of caffeine pills amongst peers by a factor of 5; 50%), low prevalence condition (half the estimated prevalence; 5%) or control condition (no information about peer prevalence). Structural equation modeling confirmed that our participants' willingness and intention to use caffeine pills in the next exam period could be explained by their past use of neuroenhancers, attitude to NE and subjective norm about use of caffeine pills whilst image of the typical user was a much less important factor. Provision of inaccurate information about prevalence reduced the predictive power of attitude with respect to willingness by 40-45%. This may be because receiving information about peer prevalence which does not fit with their perception of the social norm causes people to question their attitude. Prevalence information might exert a deterrent effect on NE via the attitude-willingness association. We argue that research into NE and deterrence of associated risk behaviors should be informed by psychological theory.
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Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest.
Bellin, MD, Freeman, ML, Gelrud, A, Slivka, A, Clavel, A, Humar, A, Schwarzenberg, SJ, Lowe, ME, Rickels, MR, Whitcomb, DC, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2014;(1):27-35
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DESCRIPTION Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure used to treat severe complications of chronic pancreatitis or very high risk of pancreatic cancer while reducing the risk of severe diabetes mellitus. However, clear guidance on indications, contraindications, evaluation, timing, and follow-up are lacking. METHODS A working group reviewed the medical, psychological, and surgical options and supporting literature related to TPIAT for a consensus meeting during PancreasFest. RESULTS Five major areas requiring clinical evaluation and management were addressed: These included: 1) indications for TPIAT; 2) contraindications for TPIAT; 3) optimal timing of the procedure; 4) need for a multi-disciplinary team and the roles of the members; 5) life-long management issues following TPIAP including diabetes monitoring and nutrition evaluation. CONCLUSIONS TPIAT is an effective method of managing the disabling complications of chronic pancreatitis and risk of pancreatic cancer in very high risk patients. Careful evaluation and long-term management of candidate patients by qualified multidisciplinary teams is required. Multiple recommendations for further research were also identified.
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Reduced self-control leads to disregard of an unfamiliar behavioral option: an experimental approach to the study of neuroenhancement.
Wolff, W, Baumgarten, F, Brand, R
Substance abuse treatment, prevention, and policy. 2013;:41
Abstract
BACKGROUND Neuroenhancement (NE), the use of psychoactive substances in order to enhance a healthy individual's cognitive functioning from a proficient to an even higher level, is prevalent in student populations. According to the strength model of self-control, people fail to self-regulate and fall back on their dominant behavioral response when finite self-control resources are depleted. An experiment was conducted to test the hypothesis that ego-depletion will prevent students who are unfamiliar with NE from trying it. FINDINGS 130 undergraduates, who denied having tried NE before (43% female, mean age = 22.76 ± 4.15 years old), were randomly assigned to either an ego-depletion or a control condition. The dependent variable was taking an "energy-stick" (a legal nutritional supplement, containing low doses of caffeine, taurine and vitamin B), offered as a potential means of enhancing performance on the bogus concentration task that followed. Logistic regression analysis showed that ego-depleted participants were three times less likely to take the substance, OR = 0.37, p = .01. CONCLUSION This experiment found that trying NE for the first time was more likely if an individual's cognitive capacities were not depleted. This means that mental exhaustion is not predictive for NE in students for whom NE is not the dominant response. Trying NE for the first time is therefore more likely to occur as a thoughtful attempt at self-regulation than as an automatic behavioral response in stressful situations. We therefore recommend targeting interventions at this inter-individual difference. Students without previous reinforcing NE experience should be provided with information about the possible negative health outcomes of NE. Reconfiguring structural aspects in the academic environment (e.g. lessening workloads) might help to deter current users.
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Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012.
Rickels, MR, Bellin, M, Toledo, FG, Robertson, RP, Andersen, DK, Chari, ST, Brand, R, Frulloni, L, Anderson, MA, Whitcomb, DC, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2013;(4):336-42
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DESCRIPTION Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. METHODS A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. RESULTS Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. CONCLUSIONS Physicians should evaluate and treat glucose intolerance in patients with pancreatitis.
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Outpatient electronic health records and the clinical care and outcomes of patients with diabetes mellitus.
Reed, M, Huang, J, Graetz, I, Brand, R, Hsu, J, Fireman, B, Jaffe, M
Annals of internal medicine. 2012;(7):482-9
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BACKGROUND Physicians can receive federal payments for meaningful use of complete certified electronic health records (EHRs). Evidence is limited on how EHR use affects clinical care and outcomes. OBJECTIVE To examine the association between use of a commercially available certified EHR and clinical care processes and disease control in patients with diabetes. DESIGN Quasi-experimental design with outpatient EHR implementation sequentially across 17 medical centers. Multivariate analyses adjusted for patient characteristics, medical center, time trends, and facility-level clustering. SETTING Kaiser Permanente Northern California, an integrated delivery system. PATIENTS 169 711 patients with diabetes mellitus. INTERVENTION Use of a commercially available certified EHR. MEASUREMENTS Drug treatment intensification and hemoglobin A(1c) (HbA(1c)) and low-density lipoprotein cholesterol (LDL-C) testing and values. RESULTS Use of an EHR was associated with statistically significant improvements in treatment intensification after HbA(1c) values of 9% or greater (odds ratio, 1.10 [95% CI, 1.05 to 1.15]) or LDL-C values of 2.6 to 3.3 mmol/L (100 to 129 mg/dL) (odds ratio, 1.06 [CI, 1.00 to 1.12]); increases in 1-year retesting for HbA(1c) and LDL-C levels among all patients, with the most dramatic change among patients with the worst disease control (HbA(1c) levels ≥9% or LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]); and decreased 90-day retesting among patients with HbA(1c) levels less than 7% or LDL-C levels less than 2.6 mmol/L (<100 mg/dL). The EHR was also associated with statistically significant reductions in HbA(1c) and LDL-C levels, with the largest reductions among patients with the worst control (0.06-mmol/L [2.19-mg/dL] reduction among patients with baseline LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]; P < 0.001). LIMITATION The EHR was implemented in a setting with strong baseline performance on cardiovascular care quality measures. CONCLUSION Use of a commercially available certified EHR was associated with improved drug treatment intensification, monitoring, and physiologic control among patients with diabetes, with greater improvements among patients with worse control and less testing in patients already meeting guideline-recommended glycemic and lipid targets. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Diseases.
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Does minimally invasive lumbar disc surgery result in less muscle injury than conventional surgery? A randomized controlled trial.
Arts, M, Brand, R, van der Kallen, B, Lycklama à Nijeholt, G, Peul, W
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2011;(1):51-7
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The concept of minimally invasive lumbar disc surgery comprises reduced muscle injury. The aim of this study was to evaluate creatine phosphokinase (CPK) in serum and the cross-sectional area (CSA) of the multifidus muscle on magnetic resonance imaging as indicators of muscle injury. We present the results of a double-blind randomized trial on patients with lumbar disc herniation, in which tubular discectomy and conventional microdiscectomy were compared. In 216 patients, CPK was measured before surgery and at day 1 after surgery. In 140 patients, the CSA of the multifidus muscle was measured at the affected disc level before surgery and at 1 year after surgery. The ratios (i.e. post surgery/pre surgery) of CPK and CSA were used as outcome measures. The multifidus atrophy was classified into three grades ranging from 0 (normal) to 3 (severe atrophy), and the difference between post and pre surgery was used as an outcome. Patients' low-back pain scores on the visual analogue scale (VAS) were documented before surgery and at various moments during follow-up. Tubular discectomy compared with conventional microdiscectomy resulted in a nonsignificant difference in CPK ratio, although the CSA ratio was significantly lower in tubular discectomy. At 1 year, there was no difference in atrophy grade between both groups nor in the percentage of patients showing an increased atrophy grade (14% tubular vs. 18% conventional). The postoperative low-back pain scores on the VAS improved in both groups, although the 1-year between-group mean difference of improvement was 3.5 mm (95% CI; 1.4-5.7 mm) in favour of conventional microdiscectomy. In conclusion, tubular discectomy compared with conventional microdiscectomy did not result in reduced muscle injury. Postoperative evaluation of CPK and the multifidus muscle showed similar results in both groups, although patients who underwent tubular discectomy reported more low-back pain during the first year after surgery.
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Cost-effectiveness of decompression according to Gill versus instrumented spondylodesis in the treatment of sciatica due to low grade spondylolytic spondylolisthesis: a prospective randomised controlled trial [NTR1300].
Arts, MP, Verstegen, MJ, Brand, R, Koes, BW, van den Akker, ME, Peul, WC
BMC musculoskeletal disorders. 2008;:128
Abstract
BACKGROUND Nerve root decompression with instrumented spondylodesis is the most frequently performed surgical procedure in the treatment of patients with symptomatic low-grade spondylolytic spondylolisthesis. Nerve root decompression without instrumented fusion, i.e. Gill's procedure, is an alternative and less invasive approach. A comparative cost-effectiveness study has not been performed yet. We present the design of a randomised controlled trial on cost-effectiveness of decompression according to Gill versus instrumented spondylodesis. METHODS/DESIGN All patients (age between 18 and 70 years) with sciatica or neurogenic claudication lasting more than 3 months due to spondylolytic spondylolisthesis grade I or II, are eligible for inclusion. Patients will be randomly allocated to nerve root decompression according to Gill, either unilateral or bilateral, or pedicle screw fixation with interbody fusion. The main primary outcome measure is the functional assessment of the patient measured with the Roland Disability Questionnaire for Sciatica at 12 weeks and 2 years. Other primary outcome measures are perceived recovery and intensity of leg pain and low back pain. The secondary outcome measures include, incidence of re-operations, complications, serum creatine phosphokinase, quality of life, medical consumption, costs, absenteeism, work perception, depression and anxiety, and treatment preference. The study is a randomised prospective multicenter trial in which two surgical techniques are compared in a parallel group design. Patients and research nurse will not be blinded during the follow-up period of 2 years. DISCUSSION Currently, nerve root decompression with instrumented fusion is the golden standard in the surgical treatment of low-grade spondylolytic spondylolisthesis, although scientific proof justifying instrumented spondylodesis over simple decompression is lacking. This trial is designed to elucidate the controversy in best surgical treatment of symptomatic patients with low-grade spondylolytic spondylolisthesis.