Publications by authors named "George Thomas"

797 Publications

Emergent chiroptical properties in supramolecular and plasmonic assemblies.

Chem Soc Rev 2021 Sep 15. Epub 2021 Sep 15.

School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram (IISER TVM), Vithura, Thiruvananthapuram, 695 551, India.

This tutorial provides a comprehensive description of the origin of chiroptical properties of supramolecular and plasmonic assemblies in the UV-visible region of the electromagnetic spectrum. The photophysical concepts essential for understanding chiroptical signatures are presented in the first section. Just as the oscillator strength (a positive quantity) is related to absorption, the rotational strength (either a positive or a negative quantity) defines the emergence of chiroptical signatures in molecular/plasmonic systems. In supramolecular systems, induced circular dichroism (ICD) originates through the off-resonance coupling of transition dipoles in chiral inclusion complexes, while exciton coupled circular dichroism (ECD) originates through the on-resonance exciton coupling of transition dipoles in chiral assemblies resulting in the formation of a bisignated CD signal. In bisignated ECD spectra, the sign of the couplet is determined not only by the handedness of chiral supramolecular assemblies, but also by the sign of the interaction energy between transition dipoles. Plasmonic chirality is briefly addressed in the last section, focusing on inherent chirality, induced chirality, and surface plasmon-coupled circular dichroism (SP-CD). The oscillator strength is of the order of 1 in molecular systems, while it becomes very large (10-10) in plasmonic systems due to the collective plasmonic excitations, resulting in intense CD signals, which can be exploited for the design of plasmonic metamaterial platforms for chiral sensing applications.
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http://dx.doi.org/10.1039/d0cs01583kDOI Listing
September 2021

Mitral valve repair in chronic severe mitral regurgitation: short-term results and analysis of mortality predictors.

Indian J Thorac Cardiovasc Surg 2021 Sep 26;37(5):506-513. Epub 2021 May 26.

Department of Cardiovascular and Thoracic Surgery, Government Medical College, Kottayam, India.

Introduction: Mitral valve repair is the accepted treatment for mitral regurgitation (MR) but lack of resources and socioeconomic concerns delay surgical referral and intervention in developing countries. We evaluated immediate and short-term results of mitral valve repair for non-ischemic MR at our centre and aimed to identify the predictors of in-hospital and follow-up mortality.

Materials And Methods: The study was conducted at a tertiary-level hospital in South India. All patients >18 years with severe non-ischemic MR who underwent mitral valve repair over a period of 6 years were included. Perioperative data was collected from hospital records and follow-up data was obtained by prospective methods.

Results: There were 244 patients (170 males). Most of the patients were in the age group 31-60 years (76.6%). Aetiology of MR was degenerative ( = 159; 65.2%), rheumatic ( = 34; 13.9%), structural ( = 42; 17.2%), or miscellaneous ( = 9; 3.7%). All patients underwent ring annuloplasty with various valve repair techniques. One hundred patients (44.7%) underwent additional cardiac procedures. At discharge, MR was moderate in 4 patients; the rest had no or mild MR. The mean hospital stay of survivors was 7.1 days (SD 2.52, range 5-25 days). There were 9 in-hospital deaths (3.68%) and 10 deaths during follow-up (4.2%). The mean follow-up period was 1.39 years, complete for 87.6%. Pre-operative left ventricle ejection fraction (LVEF) <60% ( = 0.04) was found to be significantly associated with immediate mortality. Logistic regression analysis detected age ( = 0.019), female sex ( = 0.015), and left ventricular (LV) dysfunction at discharge ( = 0.025) to be significantly associated with follow-up mortality.

Conclusion: Pre-operative LV dysfunction was identified as a significant risk factor for in-hospital mortality. Female sex, age greater than 45 years, and LV dysfunction at discharge were found to be significantly associated with follow-up mortality. Hence, it is important to perform mitral valve repair in severe regurgitation patients before significant LV dysfunction sets in for a better outcome.
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http://dx.doi.org/10.1007/s12055-021-01160-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387534PMC
September 2021

Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials.

J Natl Cancer Inst 2021 Sep 10. Epub 2021 Sep 10.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Background: Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.

Methods: Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.

Results: Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.

Conclusion: Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.
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http://dx.doi.org/10.1093/jnci/djab187DOI Listing
September 2021

Characteristics of Branch Retinal Vein Occlusion in African American Patients.

Ophthalmic Surg Lasers Imaging Retina 2021 Sep 1;52(9):492-497. Epub 2021 Sep 1.

Background And Objectives: To describe the presentation, management, and clinical outcomes of branch retinal vein occlusion (BRVO) in African American patients compared to patients of other racial or ethnic backgrounds.

Patients And Methods: This retrospective cohort study included eyes diagnosed with BRVO and macular edema at a tertiary referral center. Presenting features, treatment, and outcomes were compared based on racial or ethnic backgrounds.

Results: The study included 285 eyes: 21.8% African American, 78.2% other. African American patients were more likely to have comorbid diabetes ( = .012), open-angle glaucoma ( < .001), and to present with subretinal fluid ( = .049); multivariate analysis showed race and ethnicity alone may not fully explain presenting subretinal fluid (odds ratio = 2.807; 95% CI, 0.997 to 7.903; = .051). There was no difference in other comparisons of clinical outcomes or treatment burden, including visual acuity, duration, or treatment method.

Conclusions: Despite significant differences at presentation, the management and outcomes of BRVO did not differ significantly between African American patients and patients of other racial and ethnic backgrounds. .
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http://dx.doi.org/10.3928/23258160-20210821-01DOI Listing
September 2021

Racial Disparities Affecting Postoperative Outcomes After Brain Tumor Resection.

World Neurosurg 2021 Aug 31. Epub 2021 Aug 31.

Department of Neurosurgery, Rockefeller Neuroscience Institute, West Virginia University, Martinsburg, West Virginia. Electronic address:

Objective: To investigate racial disparities in 30-day postoperative outcomes of craniotomy for glioma resection.

Methods: 2006-2019 American College of Surgeons' National Surgical Quality Improvement Program files were queried for all patients who underwent a craniotomy for a supratentorial glioma resection. Racial disparities in preoperative variables were studied between the demographic cohorts of Asian, African Americans, Hispanics, and Caucasian. Fisher exact tests were used to examine association of preoperative variables with race. Multivariable logistic regression models, adjusted for all preoperative variables associated with race, were used to determine the odds ratios of postoperative outcomes for each demographic cohort in comparison with Caucasian patients.

Results: A total of 12,544 patients were identified: 4% Asian, 5% African American, 7% Hispanic, and 85% Caucasian. African American patients had significantly higher adjusted odds than Caucasian patients of major adverse cardiovascular events (adjusted odds ratio [aOR]: 1.827, 95% confidence interval [CI]: 1.155-2.891, P = 0.01), pulmonary events (aOR: 1.683, 95% CI: 1.145-2.473, P = 0.008), and urinary tract infection (aOR: 2.016, 95% CI: 1.221-3.327, P = 0.006). Asian patients had significantly higher odds than Caucasian patients of requiring a transfusion (aOR: 2.094, 95% CI: 1.343-3.266, P = 0.001). All demographic cohorts had higher odds of having an extended length of stay than Caucasian patients.

Conclusions: African American patients who undergo a craniotomy for glioma resection have almost twice the odds of Caucasian patients of having a postoperative major cardiovascular complication, pulmonary complication, or urinary tract infection. All minority groups have higher odds of an extended length of stay as compared with Caucasian patients.
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http://dx.doi.org/10.1016/j.wneu.2021.08.112DOI Listing
August 2021

Recurrent Atrial Tachycardias Associated With Implantable Central Venous Access Catheters in Patients With Cancer.

JACC Clin Electrophysiol 2021 Aug 17. Epub 2021 Aug 17.

Department of Medicine, Division of Cardiology, Weill Cornell Medicine - New York Presbyterian Hospital, New York, New York, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jacep.2021.06.021DOI Listing
August 2021

Cancer Patient Management during COVID-19 Pandemic: An Audit of a Single-Surgeon Unit in a COVID-Hotspot.

South Asian J Cancer 2021 Jan 21;10(1):39-41. Epub 2021 Aug 21.

Orchid Breast Health Clinic and Prashanti Cancer Care Mission, Pune, Maharashtra, India.

The report evaluates the effect of coronavirus disease (COVID-19) pandemic on breast cancer treatment and management at a single-surgeon cancer care unit in one of the hotspots of COVID-19 in India. In response to the pandemic, the adjustments were made in the clinical practice to accommodate social distancing. Patient consultations were done over phone call or in-clinic visit with prior appointment to reduce the risk of exposure to COVID-19. Total number of patients that were treated at the clinic and the essential surgeries performed during the pandemic phases are summarized in the report. The methodology adopted here for care and management of the cancer patients can serve as a guiding principle for cancer care units in the country.
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http://dx.doi.org/10.1055/s-0041-1731578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380147PMC
January 2021

Clinicopathological and Molecular Characteristics of Early-Onset Stage III Colon Adenocarcinoma: An Analysis of the ACCENT Database.

J Natl Cancer Inst 2021 Aug 18. Epub 2021 Aug 18.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Background: Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing.

Methods: Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided.

Results: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P < .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers.

Conclusion: Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.
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http://dx.doi.org/10.1093/jnci/djab123DOI Listing
August 2021

Reappraisal of electrocardiographic criteria for localization of idiopathic outflow region ventricular arrhythmias.

Heart Rhythm 2021 Aug 8. Epub 2021 Aug 8.

Division of Cardiology, Department of Medicine, Weill Cornell Medicine - New York Presbyterian Hospital, New York, New York. Electronic address:

Background: Electrocardiographic (ECG) criteria have been proposed to localize the site of origin of outflow region ventricular arrhythmias (VAs). Many factors influence the QRS morphology of VAs and may limit the accuracy of these criteria.

Objective: The purpose of this study was to assess the accuracy of ECG criteria that differentiate right from left outflow region VAs and localize VAs within the aortic sinus of Valsalva (ASV).

Methods: One hundred one patients (mean age 52 ± 16 years; 55 [54%] women) undergoing catheter ablation of right ventricular outflow tract (RVOT) or ASV VAs with a left bundle branch block, inferior axis morphology were studied. ECG measurements including V transition ratio, transition zone index, R-wave duration index, R/S amplitude index, VS/VR index, V QRS morphology, R-wave amplitude in the inferior leads were tabulated for all VAs. Comparisons were made between the predicted site of origin using these criteria and the successful ablation site.

Results: Patients had successful ablation of 71 RVOT and 38 ASV VAs. For the differentiation of RVOT from ASV VAs, the positive predictive values and negative predictive values for all tested ECG criteria ranged from 42% to 75% and from 71% to 82%, respectively, with the VS/VR index having the largest area under the curve of 0.852. Morphological QRS criteria in leads V through V did not localize ASV VAs. The maximum R-wave amplitude in the inferior leads was the sole criterion demonstrating a significant difference between right ASV, right-left ASV commissure, and left ASV sites.

Conclusion: ECG criteria for differentiating right from left ventricular outflow region VAs and for localizing ASV VAs have a limited accuracy.
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http://dx.doi.org/10.1016/j.hrthm.2021.08.003DOI Listing
August 2021

Apparent Treatment-Resistant Hypertension Assessed by Office and Ambulatory Blood Pressure in Chronic Kidney Disease-A Report from the Chronic Renal Insufficiency Cohort Study.

Kidney360 2020 Aug;1:810-818

Department of Medicine, University Hospitals Cleveland Medical Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio.

Background: Apparent treatment-resistant hypertension is common in patients with CKD. Whether measurement of 24-hour ambulatory BP monitoring is valuable for risk-stratifying patients with resistant hypertension and CKD is unclear.

Methods: We analyzed data from the Chronic Renal Insufficiency Cohort study, a prospective study of participants (=1186) with CKD. Office BP was measured using standardized protocols; ambulatory BP was measured using Spacelabs monitors. Apparent treatment-resistant hypertension was defined on the basis of office BP, ambulatory BP monitoring, and use of more than three antihypertensive medications. Outcomes were composite cardiovascular disease, kidney outcomes, and mortality. Groups were compared using Cox regression analyses with a control group of participants without apparent treatment-resistant hypertension.

Results: Of 475 participants with apparent treatment-resistant hypertension on the basis of office BP, 91.6% had apparent treatment-resistant hypertension confirmed by ambulatory BP monitoring. Unadjusted event rates of composite cardiovascular disease, kidney outcomes, and mortality were higher in participants with ambulatory BP monitoring-defined apparent treatment-resistant hypertension compared with participants without apparent treatment-resistant hypertension. In adjusted analyses, the risks of composite cardiovascular disease (hazard ratio, 1.27; 95% confidence interval [95% CI], 0.59 to 2.7), kidney outcomes (hazard ratio, 1.68; 95% CI, 0.88 to 3.21), and mortality (hazard ratio, 1.27; 95% CI, 0.5 to 3.25) were not statistically significantly higher in participants with ambulatory BP monitoring-defined apparent treatment-resistant hypertension compared with participants without apparent treatment-resistant hypertension.

Conclusions: In our study population with CKD, most patients with apparent treatment-resistant hypertension defined on the basis of office BP have apparent treatment-resistant hypertension confirmed by ambulatory BP monitoring. Although ABPM-defined apparent treatment-resistant hypertension was not independently associated with clinical outcomes, it identified participants at high risk for adverse clinical outcomes.
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http://dx.doi.org/10.34067/KID.0002072020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298012PMC
August 2020

Proton-pump inhibitor vs. H2-receptor blocker use and overall risk of CKD progression.

BMC Nephrol 2021 Jul 15;22(1):264. Epub 2021 Jul 15.

Cleveland Clinic, Cleveland, OH, USA.

Background: The relationship between proton-pump inhibitor (PPI) use and chronic kidney disease (CKD) progression remains controversial. Specifically, there is a lack of data evaluating renal outcomes in established CKD patients. The aim of our study is to determine the risk of progression to end-stage kidney disease (ESKD) or death amongst CKD patients on PPI, histamine-2 receptor blocker (H2B), or no anti-acid therapy.

Methods: Using our CKD registry, we evaluated the relationship between PPI and H2B use and outcomes amongst patients with CKD (eGFR < 60), with at least 2 PCP visits in the year prior. A Cox proportional hazards model was used to evaluate the relationship between medication groups and overall mortality, while competing risks regression models were used to determine the risk of ESKD with death as a competing risk.

Results: 25,455 patients met inclusion criteria and were stratified according to medication group: no antacid therapy (15,961), PPI use (8646), or H2B use (848). At 4 years, the cumulative incidence of ESKD with death as a competing risk was 2.0% (95% CI: 1.7, 2.4), 1.5% (0.8, 2.8), and 1.6%(1.4, 1.9) among PPI, H2B, and no medication respectively (P = 0.22). The cumulative incidence of death with ESKD as a competing risk was 17.6% (95% CI: 16.6, 18.6), 16.7% (13.7, 19.8), and 17.3% (16.6, 18.0) (P = 0.71).

Conclusions: Use of PPI in a CKD population was not associated with increased mortality or progression to ESKD when compared to H2 blocker and to no acid suppressing therapy.
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http://dx.doi.org/10.1186/s12882-021-02449-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281649PMC
July 2021

Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Aug;7(8):1225-1230

NRG Oncology, Philadelphia, Pennsylvania.

Importance: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed.

Objective: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone.

Design, Setting, And Participants: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020.

Interventions: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery.

Main Outcomes And Measures: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety).

Results: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found.

Conclusions And Relevance: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study.

Trial Registration: ClinicalTrials.gov Identifier: NCT02921256.
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http://dx.doi.org/10.1001/jamaoncol.2021.1683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251652PMC
August 2021

Key changes to improve social presence of a virtual health assistant promoting colorectal cancer screening informed by a technology acceptance model.

BMC Med Inform Decis Mak 2021 06 22;21(1):196. Epub 2021 Jun 22.

STEM Translational Communication Center (STCC), University of Florida, Weimer Hall 2043, PO Box 118400, Gainesville, FL, 32611, USA.

Background: Understanding how older, minoritized patients attend to cues when interacting with web-based health messages may provide opportunities to improve engagement with novel health technologies. We assess acceptance-promoting and acceptance-inhibiting cues of a web-based, intervention promoting colorectal cancer (CRC) screening with a home stool test among Black women.

Materials And Methods: Focus group and individual interview data informed iterative changes to a race- and gender-concordant virtual health assistant (VHA). A user-centered design approach was used across 3 iterations to identify changes needed to activate cues described as important; such as portraying authority and expertise. Questionnaire data were analyzed using non-parametric tests for perceptions of cues. Analysis was guided by the Technology Acceptance Model.

Results: Perceptions of interactivity, social presence, expertise, and trust were important cues in a VHA-delivered intervention promoting CRC screening. Features of the web-based platform related to ease of navigation and use were also discussed. Participant comments varied across the 3 iterations and indicated acceptance of or a desire to improve source cues for subsequent iterations. We highlight the specific key changes made at each of three iterative versions of the interactive intervention in conjunction with user perception of changes.

Discussion: Virtual agents can be adapted to better meet patient expectations such as being a trustworthy and expert source. Across three evolving versions of a Black, VHA, cues for social presence were particularly important. Social presence cues helped patients engage with CRC screening messages delivered in this novel digital context.

Conclusions: When using a VHA to disseminate health information, cues associated with acceptability can be leveraged and adapted as needed for diverse audiences. Patient characteristics (age, identity, health status) are important to note as they may affect perceptions of a novel health technologies ease of use and relevancy according to the leading models.
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http://dx.doi.org/10.1186/s12911-021-01549-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218395PMC
June 2021

Targeting the Standardized Blood Pressure: New Guidelines for Blood Pressure Management in Chronic Kidney Disease.

Ann Intern Med 2021 Sep 22;174(9):1321-1322. Epub 2021 Jun 22.

Glickman Urological and Kidney Institute, Cleveland Clinic Cleveland, Ohio.

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http://dx.doi.org/10.7326/M21-2571DOI Listing
September 2021

The Production, Efficacy, and Safety of Machine-Generated Bicarbonate Solution for Continuous Venovenous Hemodialysis (CVVHD): The Cleveland Clinic Method.

Kidney Med 2021 May-Jun;3(3):353-359.e1. Epub 2021 Mar 10.

Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, OH.

Rationale & Objective: Since 1994, the Nephrology and Hypertension Department at the Cleveland Clinic has prepared and used bicarbonate-based solution for continuous venovenous hemodialysis (CVVHD) using a standard volumetric hemodialysis machine rather than purchasing from a commercial vendor. This report describes the process of producing Cleveland Clinic UltraPure Solution (CCUPS), quality and safety monitoring, economic costs, and clinical outcomes.

Study Design: Retrospective study.

Setting & Participants: CVVHD experience at Cleveland Clinic, focusing on dialysate production, institutional factors, and patients requiring continuous kidney replacement therapy. Production is shown at www.youtube.com/watch?v=WGQgephMEwA.

Outcomes: Feasibility, safety , and cost.

Results: Of 6,426 patients treated between 2011 and 2019 with continuous kidney replacement therapy, 59% were men, 71% were White, 40% had diabetes mellitus, and 74% presented with acute kidney injury. 98% of patients were treated with CVVHD using CCUPS, while the remaining 2% were treated with either continuous venovenous hemofiltration or continuous venovenous hemodiafiltration using commercial solution. The prescribed and delivered effluent doses were 24.8 (IQR) versus 20.7 mL/kg/h (IQR), respectively. CCUPS was as effective in restoring electrolyte and serum bicarbonate levels and reducing phosphate, creatinine, and serum urea nitrogen levels as compared with packaged commercial solution over a 3-day period following initiation of dialysis, with a comparable effluent dose. Among those with acute kidney injury, mortality was similar to that predicted with the 60-day acute kidney injury predicted mortality score (r = 0.997; CI: 0.989-0.999). At our institution, the cost of production for 1 L of CCUPS is $0.67, which is considerably less than the cost of commercially purchased fluid.

Limitations: Observational design without a rigorous control group.

Conclusions: CVVHD using locally generated dialysate is safe and cost-effective.
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http://dx.doi.org/10.1016/j.xkme.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178460PMC
March 2021

Phase II Study of 5-Fluorouracil, Oxaliplatin plus Dasatinib (FOLFOX-D) in First-Line Metastatic Pancreatic Adenocarcinoma.

Oncologist 2021 Jun 8. Epub 2021 Jun 8.

Department of Surgery, Virginia Commonwealth University, Richmond, Virginia, USA.

Lessons Learned: Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders.

Background: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D).

Methods: In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls.

Results: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%).

Conclusion: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.
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http://dx.doi.org/10.1002/onco.13853DOI Listing
June 2021

Breast cancer biobank from a single institutional cohort in an urban setting in india: Tumor characteristics and survival outcomes.

Cancer Treat Res Commun 2021 1;28:100409. Epub 2021 Jun 1.

Prashanti Cancer Care Mission, Pune; Center for Translational Cancer Research, a Joint venture between Prashanti Cancer Care Mission and IISER Pune. Electronic address:

Background: A breast cancer biobank with retrospectively collected patient data and FFPE tissue samples was established in 2018 at Prashanti Cancer Care Mission, Pune, India. It runs a cancer care clinic with support from a single surgeon's breast cancer practice. The clinical data and tissue sample collection is undertaken with appropriate patient consent following ethical approval and guidelines.

Methods: The biobank holds clinical history, diagnostic reports, treatment and follow-up information along with FFPE tumor tissue specimens, adjacent normal and, in few cases, contralateral normal breast tissue. Detailed family history and germline mutational profiles of eligible and consenting patients and their relatives are also deposited in the biobank.

Results: Here, we report the first audit of the biobank. A total number of 994 patients with breast disease have deposited consented clinical records in the biobank. The majority of the records (80%, n = 799) are of patients with infiltrating ductal carcinoma (IDC). Of 799 IDC patients, 434 (55%) have deposited tumor tissue in the biobank with consent. In addition, germline mutation profiles of 84 patients and their family members are deposited. Follow-up information is available for 85% of the 434 IDC patients with an average follow-up of 3 years.

Conclusion: The biobank has aided the initiation of translational research at our center in collaboration with eminent institutes like IISER Pune and SJRI Bangalore to evaluate profiles of breast cancer in an Indian cohort. The biobank will be a valuable resource to the breast cancer research community, especially to understand South Asian profiles of breast cancer.
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http://dx.doi.org/10.1016/j.ctarc.2021.100409DOI Listing
June 2021

A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment.

Cancer Chemother Pharmacol 2021 Sep 7;88(3):485-497. Epub 2021 Jun 7.

Division of Hematology-Oncology, University of California, Los Angeles, CA, USA.

Purpose: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance.

Methods: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m twice daily.

Results: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs.

Conclusion: FTD/TPI is safe and tolerable at the recommended 35 mg/m dose in patients with mild/moderate RI and at the reduced 20 mg/m dose in patients with severe RI.

Trial Registration: NCT02301117, registration date: November 21, 2014.
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http://dx.doi.org/10.1007/s00280-021-04308-zDOI Listing
September 2021

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma.

Cell Rep Med 2021 May 7;2(5):100267. Epub 2021 May 7.

Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression . Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.
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http://dx.doi.org/10.1016/j.xcrm.2021.100267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149375PMC
May 2021

Ethical issues in randomised trials in surgery.

Authors:
George Thomas

Indian J Med Ethics 2021 Jan-Mar;VI(1):1-5

Head of Orthopaedics and Emergency Services, St. Isabel's Hospital, Mylapore, Chennai, Tamil Nadu 600 004 INDIA.

Clinical trials are required in surgery to evaluate existing procedures and to assess the value of new techniques. Except for observational studies which are considered useful only to propose a hypothesis, all study designs require a comparator group. The randomised controlled trial (RCT) is recognised as the most robust study design. There are specific ethical difficulties in conducting RCTs.
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http://dx.doi.org/10.20529/IJME.2020.099DOI Listing
June 2021

Lattice Vibrations and Time-Dependent Evolution of Local Phonon Modes during Exciton Formation in Conjugated Polymeric Molecules.

Polymers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Department of Chemistry & Biochemistry and Physics & Astronomy, University of Missouri-St. Louis, St. Louis, MO 63121, USA.

Based on nonadiabatic molecular dynamics that integrate electronic transitions with the time-dependent phonon spectrum, this article provides a panoramic landscape of the dynamical process during the formation of photoinduced excitons in conjugated polymers. When external optical beam/pulses with intensities of 10 µJ/cm and 20 µJ/cm are utilized to excite a conjugated polymer, it is found that the electronic transition firstly triggers local lattice vibrations, which not only locally distort alternating bonds but change the phonon spectrum as well. Within the first 60 fs, the occurrence of local distortion of alternating bonds accompanies the localization of the excited-state's electron. Up to 100 fs, both alternating bonds and the excited electronic state are well localized in the middle of the polymer chain. In the first ~200 fs, the strong lattice vibration makes a local phonon mode at 1097.7 cm appear in the phonon spectrum. The change of electron states then induces the self-trapping effect to act on the following photoexcitation process of 1.2 ps. During the following relaxation of 1.0 ps, new local infrared phonon modes begin to occur. All of this, incorporated with the occurrence of local infrared phonon modes and localized electronic states at the end of the relaxation, results in completed exciton formation.
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http://dx.doi.org/10.3390/polym13111724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197373PMC
May 2021

Exploring the feasibility of using real-world data from a large clinical data research network to simulate clinical trials of Alzheimer's disease.

NPJ Digit Med 2021 May 14;4(1):84. Epub 2021 May 14.

Health Outcomes & Biomedical Informatics, University of Florida, Gainesville, FL, USA.

In this study, we explored the feasibility of using real-world data (RWD) from a large clinical research network to simulate real-world clinical trials of Alzheimer's disease (AD). The target trial (i.e., NCT00478205) is a Phase III double-blind, parallel-group trial that compared the 23 mg donepezil sustained release with the 10 mg donepezil immediate release formulation in patients with moderate to severe AD. We followed the target trial's study protocol to identify the study population, treatment regimen assignments and outcome assessments, and to set up a number of different simulation scenarios and parameters. We considered two main scenarios: (1) a one-arm simulation: simulating a standard-of-care (SOC) arm that can serve as an external control arm; and (2) a two-arm simulation: simulating both intervention and control arms with proper patient matching algorithms for comparative effectiveness analysis. In the two-arm simulation scenario, we used propensity score matching controlling for baseline characteristics to simulate the randomization process. In the two-arm simulation, higher serious adverse event (SAE) rates were observed in the simulated trials than the rates reported in original trial, and a higher SAE rate was observed in the 23 mg arm than in the 10 mg SOC arm. In the one-arm simulation scenario, similar estimates of SAE rates were observed when proportional sampling was used to control demographic variables. In conclusion, trial simulation using RWD is feasible in this example of AD trial in terms of safety evaluation. Trial simulation using RWD could be a valuable tool for post-market comparative effectiveness studies and for informing future trials' design. Nevertheless, such an approach may be limited, for example, by the availability of RWD that matches the target trials of interest, and further investigations are warranted.
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http://dx.doi.org/10.1038/s41746-021-00452-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121837PMC
May 2021

The association between cognitive impairment and breast and colorectal cancer screening utilization.

BMC Cancer 2021 May 12;21(1):539. Epub 2021 May 12.

Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, 2004 Mowry Road, PO Box 100177, Gainesville, FL, 32610, USA.

Background: Undergoing cancer screening is a debatable topic in patients with cognitive impairment. In this study, we aimed to examine the utilization and predictors of breast and colorectal cancer screening among screening eligible, cognitively impaired individuals.

Methods: We analyzed the 2018 and 2019 National Health Interview Survey data (n = 12,965 and 24,782, respectively) on individuals eligible for breast or colorectal cancer screening. We calculated the percentage of cancer screening eligible individuals who received mammogram or colonoscopy by cognitive impairment status. We used multivariable logistic regression to examine whether having a recent mammogram or colonoscopy differed by cognitive impairment status, adjusting for covariates.

Results: We observed a significantly lower percentage of mammogram use in the screening eligible, cognitively impaired (mild or severe) versus unimpaired women. Adjusting for the covariates, the cognitively impaired women, mild (odds ratio [OR] = 0.85; p = 0.015) or severe (OR = 0.54; p <  0.001), were less likely to have had a recent mammogram compared to the cognitively unimpaired women. Although statistically non-significant, the percentage of colonoscopy use in the screening eligible, cognitively impaired individuals were slightly higher than that in the cognitively unimpaired individuals. In the regression analysis, we found the cognitively impaired men, mild (OR = 0.79; p <  0.001) or severe (OR = 0.69; p = 0.038), were less likely to have had a recent colonoscopy compared to the cognitively unimpaired men. More studies are needed to examine the multilevel factors that underpin the difference in cancer screening utilization in this vulnerable population.

Conclusion: Our results highlight the need for additional research to address utilization and effectiveness of cancer screening in individuals with cognitive impairment.
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http://dx.doi.org/10.1186/s12885-021-08321-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114528PMC
May 2021

Incidence of Hyperglycemia/Secondary Diabetes in Women who have Undergone Curative Chemotherapy for Breast Cancer: First Study from India.

South Asian J Cancer 2020 Jul 19;9(3):130-135. Epub 2021 Mar 19.

Research Unit, Mangalore Institute of Oncology, Mangalore, Karnataka, India.

 Development of cancer chemotherapy treatment-induced hyperglycemia/ diabetes (secondary diabetes) is a major problem and has never been reported from India. The present study was planned to ascertain this in women undergoing curative chemotherapy for their breast cancer.  This was a retrospective chart-based study and was conducted in a cancer specialty hospital. The information on women who were nondiabetic at the start of the treatment was collected from the files. Details on cancer diagnosis, domicile, body mass index (BMI), type of diet, marital status, number of children, and previous history of diabetes if any were considered. The blood glucose levels before surgery and after the completion of radiotherapy were considered. World Health Organization (WHO) guidelines for diabetes were considered. The data were subjected to frequency and percentage and analyzed using Chi-square test. Association between the demographic details and development of Hyperglycemia or secondary diabetes or prediabetes was done using the Pearson's correlation analysis. < 0.05 was considered as statistically significant.  A total of 474 cases were included in accordance with the inclusion criteria. The results indicated that by the end of the radiation treatment, 24.89% were prediabetic, 10.97% were diabetic after being in prediabetic stage, 8.22% became diabetic without going through a prediabetic stage, and that 55.91% did not develop either prediabetic or diabetic condition. Analysis of development of secondary diabetes and prediabetes with BMI ( < 0.0001) and age ( < 0.024) showed a strong correlation and was significant.  To the best of the authors' knowledge, this is the first study from India, and the results indicate that the development of secondary diabetes in women undergoing curative chemotherapy is high. Attempts are underway to ascertain the cause for the development and how it can be mitigated.
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http://dx.doi.org/10.1055/s-0041-1723104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075627PMC
July 2020

Using Real-World Data to Rationalize Clinical Trials Eligibility Criteria Design: A Case Study of Alzheimer's Disease Trials.

AMIA Annu Symp Proc 2020 25;2020:717-726. Epub 2021 Jan 25.

University of Florida, Gainesville, Florida, USA.

Low trial generalizability is a concern. The Food and Drug Administration had guidance on broadening trial eligibility criteria to enroll underrepresented populations. However, investigators are hesitant to do so because of concerns over patient safety. There is a lack of methods to rationalize criteria design. In this study, we used data from a large research network to assess how adjustments of eligibility criteria can jointly affect generalizability and patient safety (i.e the number of serious adverse events [SAEs]). We first built a model to predict the number of SAEs. Then, leveraging an a priori generalizability assessment algorithm, we assessed the changes in the number of predicted SAEs and the generalizability score, simulating the process of dropping exclusion criteria and increasing the upper limit of continuous eligibility criteria. We argued that broadening of eligibility criteria should balance between potential increases of SAEs and generalizability using donepezil trials as a case study.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075542PMC
June 2021

A Pilot Study Examining the Efficacy of Delivering Colorectal Cancer Screening Messages via Virtual Health Assistants.

Am J Prev Med 2021 08 20;61(2):251-255. Epub 2021 Apr 20.

Department of Computer & Information Science & Engineering, College of Engineering, University of Florida, Gainesville, Florida.

Introduction: Patients are more likely to complete colorectal cancer screening when recommended by a race-concordant healthcare provider. Leveraging virtual healthcare assistants to deliver tailored screening interventions may promote adherence to colorectal cancer screening guidelines among diverse patient populations. The purpose of this pilot study is to determine the efficacy of the Agent Leveraging Empathy for eXams virtual healthcare assistant intervention to increase patient intentions to talk to their doctor about colorectal cancer screening. It also examines the influence of animation and race concordance on intentions to complete colorectal cancer screening.

Methods: White and Black adults (N=1,363) aged 50-73 years and not adherent to colorectal cancer screening guidelines were recruited from Qualtrics Panels in 2018 to participate in a 3-arm (animated virtual healthcare assistant, static virtual healthcare assistant, attention control) message design experiment. In 2020, a probit regression model was used to identify the intervention effects.

Results: Participants assigned to the animated virtual healthcare assistant (p<0.01) reported higher intentions to talk to their doctor about colorectal cancer screening than participants assigned to the other conditions. There was a significant effect of race concordance on colorectal cancer screening intentions but only in the static virtual healthcare assistant condition (p=0.04). Participant race, age, trust in healthcare providers, health literacy, and cancer information overload were also significant predictors of colorectal cancer screening intentions.

Conclusions: Animated virtual healthcare assistants were efficacious compared with the static virtual healthcare assistant and attention control conditions. The influence of race concordance between source and participant was inconsistent across conditions. This warrants additional investigation in future studies given the potential for virtual healthcare assistant‒assisted interventions to promote colorectal cancer screening within guidelines.
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http://dx.doi.org/10.1016/j.amepre.2021.01.014DOI Listing
August 2021

A Subjective Culture Approach to Cancer Prevention: Rural Black and White Adults' Perceptions of Using Virtual Health Assistants to Promote Colorectal Cancer Screening.

Health Commun 2021 Apr 20:1-12. Epub 2021 Apr 20.

STEM Translational Communication Center, University of Florida.

In the US, Black adults are less likely than White adults to be screened for colorectal cancer (CRC). This study uses a subjective culture approach to describe and compare perceptions of a CRC screening intervention delivered via virtual health assistants (VHAs) among rural Black and White study participants. We analyzed 28 focus groups with Black ( = 85) and White ( = 69) adults aged 50-73. Participants, largely recruited through community engagement efforts, tested the VHA intervention on mobile phones provided by the research team. Moderated discussions were recorded, transcribed, and analyzed using thematic analysis. All groups preferred the VHA to be friendly. Other important cues included trustworthiness, authority, and expertise. Black participants expressed a preference for receiving information about their CRC risk from the VHA compared with White adults. Black participants also expressed the importance of sharing the intervention and the CRC screening messages with younger members of their networks, including family members who could benefit from screening messages before reaching the recommended age for screening. The key similarities and differences between Black and White adults' perceptions of the intervention that were identified in this study can help inform future efforts to develop effective communication strategies and reduce cancer screening inequities.
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http://dx.doi.org/10.1080/10410236.2021.1910166DOI Listing
April 2021

Novel CRISPR-Cas Systems: An Updated Review of the Current Achievements, Applications, and Future Research Perspectives.

Int J Mol Sci 2021 Mar 24;22(7). Epub 2021 Mar 24.

Department of Molecular and Cellular Engineering, Jacob Institute of Biotechnology and Bioengineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India.

According to Darwin's theory, endless evolution leads to a revolution. One such example is the Clustered Regularly Interspaced Palindromic Repeats (CRISPR)-Cas system, an adaptive immunity system in most archaea and many bacteria. Gene editing technology possesses a crucial potential to dramatically impact miscellaneous areas of life, and CRISPR-Cas represents the most suitable strategy. The system has ignited a revolution in the field of genetic engineering. The ease, precision, affordability of this system is akin to a Midas touch for researchers editing genomes. Undoubtedly, the applications of this system are endless. The CRISPR-Cas system is extensively employed in the treatment of infectious and genetic diseases, in metabolic disorders, in curing cancer, in developing sustainable methods for fuel production and chemicals, in improving the quality and quantity of food crops, and thus in catering to global food demands. Future applications of CRISPR-Cas will provide benefits for everyone and will save countless lives. The technology is evolving rapidly; therefore, an overview of continuous improvement is important. In this review, we aim to elucidate the current state of the CRISPR-Cas revolution in a tailor-made format from its discovery to exciting breakthroughs at the application level and further upcoming trends related to opportunities and challenges including ethical concerns.
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http://dx.doi.org/10.3390/ijms22073327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036902PMC
March 2021

Our evolving understanding of primary aldosteronism.

Cleve Clin J Med 2021 04 1;88(4):221-227. Epub 2021 Apr 1.

Department of Nephrology and Hypertension, Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, OH; Assistant Professor, Cleveland Clinic Lerner College of Case Western Reserve University, Cleveland, OH.

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http://dx.doi.org/10.3949/ccjm.88a.20166DOI Listing
April 2021

Characterizing advanced breast cancer heterogeneity and treatment resistance through serial biopsies and comprehensive analytics.

NPJ Precis Oncol 2021 Mar 26;5(1):28. Epub 2021 Mar 26.

Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.

Molecular heterogeneity in metastatic breast cancer presents multiple clinical challenges in accurately characterizing and treating the disease. Current diagnostic approaches offer limited ability to assess heterogeneity that exists among multiple metastatic lesions throughout the treatment course. We developed a precision oncology platform that combines serial biopsies, multi-omic analysis, longitudinal patient monitoring, and molecular tumor boards, with the goal of improving cancer management through enhanced understanding of the entire cancer ecosystem within each patient. We describe this integrative approach using comprehensive analytics generated from serial-biopsied lesions in a metastatic breast cancer patient. The serial biopsies identified remarkable heterogeneity among metastatic lesions that presented clinically as discordance in receptor status and genomic alterations with mixed treatment response. Based on our study, we highlight clinical scenarios, such as rapid progression or mixed response, that indicate consideration for repeat biopsies to evaluate intermetastatic heterogeneity (IMH), with the objective of refining targeted therapy. We present a framework for understanding the clinical significance of heterogeneity in breast cancer between metastatic lesions utilizing multi-omic analyses of serial biopsies and its implication for effective personalized treatment.
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http://dx.doi.org/10.1038/s41698-021-00165-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997873PMC
March 2021
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