tbuckley/cabot-search huggingface dataset:
Estimating the Lifetime Benefits of Treatments for Heart Failure
Authors: João Pedro Ferreira, Kieran F. Docherty, Susan Stienen, Pardeep S. Jhund, Brian L. Claggett, Scott D. Solomon, Mark C. Petrie, John Gregson, Stuart J. Pocock, Faiez Zannad, John J.V. McMurray
Journal: JACC Heart Failure (2020)

This study compared ways of describing treatment effects. The objective was to better explain to clinicians and patients what they might expect from a given treatment, not only in terms of relative and absolute risk reduction, but also in projections of long-term survival.The restricted mean survival time (RMST) can be used to estimate of long-term survival, providing a complementary approach to more conventional metrics (e.g., absolute and relative risk), which may suggest greater benefits of therapy in high-risk patients compared with low-risk patients.Relative and absolute risk, as well as the RMST, were calculated in heart failure with reduced ejection fraction (HFrEF) trials.As examples, in the RALES trial (more severe HFrEF), the treatment effect metrics for spironolactone versus placebo on heart failure hospitalization and/or cardiovascular death were a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.5 to 0.77), number needed to treat = 9 (7 to 14), and age extension of event-free survival +1.1 years (-0.1 to + 2.3 years). The corresponding metrics for EMPHASIS-HF (eplerenone vs. placebo in less severe HFrEF) were 0.64 (0.54 to 0.75), 14 (1 to 22), and +2.9 (1.2 to 4.5). In patients in PARADIGM-HF aged younger than 65 years, the metrics for sacubitril/valsartan versus enalapril were 0.77 (95% CI: 0.68 to 0.88), 23 (15 to 44), and +1.7 (0.6 to 2.8) years; for those aged 65 years or older, the metrics were 0.83 (95% CI: 0.73 to 0.94), 29 (17 to 83), and +0.9 (0.2 to 1.6) years, which provided evidence of a greater potential life extension in younger patients. Similar observations were found for lower risk patients.RMST event-free (and overall) survival estimates provided a complementary means of evaluating the effect of therapy in relation to age and risk. They also provided a clinically useful metric that should be routinely reported and used to explain the potential long-term benefits of a given treatment, especially to younger and less symptomatic patients.
Baseline cancer worry and tumor marker testing among earlier-stage breast cancer patients participating in a Choosing Wisely pilot.
Authors: Karma L. Kreizenbeck, Kathryn Egan, Tracy Wong, Barbara Jagels, Barbara Jensen, Julie C. Smith, Blair Billings Irwin, Heather Noble, Scott David Ramsey
Journal: Journal of Clinical Oncology (2020)

153 Background: We developed a patient-facing video aimed at raising early breast cancer survivors’ adherence to ASCO’s Choosing Wisely recommendation against surveillance tumor marker testing. To understand the impact of the video on cancer worry regarding recurrence, we surveyed breast cancer survivors before and after viewing the video. Methods: Women with stage I-IIIA breast cancer (N=246) treated at six regional community clinics were surveyed prior to viewing a video at the start of surveillance, then again at follow-up one year later (N=171). Both surveys included the Cancer Worry Scale (CWS-8 items, 4-point Likert scale). Tumor marker (TM) testing during surveillance was collected for 728 patients and linked to surveys among those who provided consent (N=105). Results: Most women (77%) were white age 50+. Among women who completed both questionnaires (N=153), the average CWS summary score was 17.1 at baseline (range=9-29) and 16.9 at follow-up ( p=0.48, range=8-30). Women who did not view the video (A) and those with high baseline cancer worry (B) who viewed the video had similar rates of TM testing (19%) compared to patients with low baseline cancer worry (C) who viewed the video (3%). Cancer worry is highly correlated with the decision to use of TM testing. Viewing an informational video that provided evidence-based advice on follow-up and testing did not impact cancer worry. Enrollment among eligible patients was impacted by challenges to proactively identify and consent patients during their transition to surveillance. Conclusions: Patients with high baseline cancer worry may need different or additional guidance beyond an educational video during their transition to surveillance for breast cancer. [Table: see text]
Preserving innate memory to overcomeSARS-CoV-2 infection through the mevalonate pathway
Authors: Juan Luis Gomez, Adam Brufsky
Journal: Clinical Cancer Research (2020)

Background: Easily accessible therapies have been proposed to treat SARS-CoV-2 infection  Given that themevalonate pathway is critical in preventing nonspecific inflammation, events that interfere in this pathway inmononuclear or epithelial lung cells might determine the outcome of infected patients  Based on its mechanism ofaction, we hypothesize that in patients with metastatic cancer (MC), zoledronic acid (ZA) may influence the severityof COVID-19 disease  Methods: In silico analysis compared normalized expression levels of prenylation-related genes in mononuclearand epithelial cells, between infected and noninfected SARS-CoV and SARS-CoV-2 samples, from available GEOdatasets  RNA analysis was done using R v3 6 3  Counts were normalized with EdgeR, and ggpubr package and was used to compute t-tests  For analyzing samples from GSE150728, Partek Flow was used to align and normalizereads from single-cell RNA  Results: Analysis of data from the 2003 SARS outbreak (GSE1739) showed that PBMCs isolated from infectedpatients expressed lower levels of HMGCR, FNTA, COX10, and PGGT1B (1 5-fold as compared to their healthy controls  Infected A549cells showed decreased levels of MVK and RABGGTA (p<0 05)  In SARS-CoV-2-infected A549 cells, ACE2transduction upregulated RABGGTA, HMGCR, COX10, and RAB27B when compared to non-transduced infectedcells  This suggested that downregulation of prenylation might occur upon binding of the viral spike protein to theACE2 receptor  Finally, we analyzed single-cell RNA-seq transcripts from uninfected PBMCs (no SARS reads)isolated from acutely ill SARS-CoV-2 patients (GSE150728)  Here, we found no differences in the expression of anyof these genes  This suggests that disruption of the mevalonate pathway may only account to infected cells  Conclusion: In light of these findings, coronaviruses may hijack the mevalonate pathway and induce autoimmunity Response to coronavirus infection may differ in patients with MC under treatment with ZA, statins, or othersubstances that interfere with prenylation-mediated small vesicle trafficking (i e , hydroxychloroquine, nicotine) Hence, studies that investigate SARS-CoV-2 disease severity in patients under treatment with ZA are stronglyneeded
Carcinogenicity of opium consumption
Authors: Saman Warnakulasuriya, Deirdre Cronin-Fenton, Jennifer Jinot, Farin Kamangar, Reza Malekzadeh, Nazir A Dar, Arash Etemadi, Paola Fortini, Deborah C Glass, Narges Khanjani, Ruri Kikura-Hanajiri, Nuria Malats, Akram Pourshams, Afarin Rahimi-Movaghar, David B Richardson, Vikash Sewram, Jennifer Girschik, Michelle C Turner, Eero Suonio, Yann Grosse, Lamia Benbrahim-Tallaa, Mahdi Sheikh, Bayan Hosseini, MengMeng Li, Heidi Mattock, Kathryn Z Guyton, Mary K Schubauer-Berigan
Journal: The Lancet Oncology (2020)
Differences in rates of low-dose computed tomography screening for lung cancer amongst various outpatient care centers.
Authors: Lukas Delasos, Anna Kookoolis, Meghana Singh, Alla Turshudzhyan, Nerea Lopetegui-Lia, Radhika Kulkarni
Journal: Journal of Clinical Oncology (2020)

245 Background: Despite low-dose computed tomography (LDCT) screening for lung cancer recommended by the United States Preventive Services Task Force (USPSTF) demonstrating a relative reduction in mortality, there remains low rates of testing nationwide. Yet studies are limited regarding specific differences in screening rates amongst various outpatient care settings. Methods: We performed retrospective chart reviews of patients followed by resident providers within an academic internal medicine residency program who met USPSTF guidelines for lung cancer screening between 2015-2020. This was conducted at three separate outpatient clinic sites including a state-funded academic institution, inner city community health center, and veteran affairs medical center. Data collection included patient demographic and smoking histories as well as rates of ordered and completed LDCT screening. Results: A total of 832 patients were identified as current or former smokers between the ages of 55 and 80 years: 320 from Hartford Hospital Community Health Center (HHCHC), 262 from University of Connecticut Health Center (UCHC), and 250 from the Veteran Affairs (VA) Medical Center. 85 (27%) of these patients from HHCHC, 84 (32%) from UCHC, and 56 (22%) from the VA met USPSTF eligibility criteria for LDCT screening. Overall compliance rates of screening were found to be 44% at HHCHC, 59.5% at UCHC, and 51.8% at the VA. Results are outlined in Table. Conclusions: Screening rates for lung cancer with LDCT remain low but have been steadily improving throughout the United States following new recommendations and increased awareness provided by multiple medical organizations. We sought to compare differences in compliance rates amongst various outpatient clinics within the same internal medicine residency program at University of Connecticut. Our findings demonstrate significant differences in LDCT screening for lung cancer between the program’s community health center versus its state and federally funded outpatient clinics. Automatic reminders to providers can potentially improve rates of lung cancer screening. Patients should also be educated about the importance of screening to improve adherence with imaging. [Table: see text]
Medical cost of care by line of treatment (LoT) in Medicare Fee-for-Service (FFS) beneficiaries with <i>KRAS</i>-mutated metastatic non-small cell lung cancer (mNSCLC).
Authors: Tara Matsuda, Aurelien Jamotte, Ann Xi, Barton Jones, Allison Petrilla, Nathan Markward, Anne Murunga, Kendall Lee Stevinson
Journal: Journal of Clinical Oncology (2020)

63 Background: While no targeted therapy is currently approved for patients with KRAS-mutated mNSCLC, new therapies are being developed for patients with KRAS p.G12C-mutated NSCLC. However, real-world evidence on cost of care in managing this population is currently lacking. This study addresses this gap by describing costs of mNSCLC patients with KRAS mutations, stratified by LoT and relative to exposure to a PD(L)1 inhibitor [PD(L)1i]. Methods: Medicare FFS claims (100% sample, Parts A/B) and the PROGNOS NSCLC Explorer dataset were linked to identify patients with mNSCLC, a positive KRAS biomarker test result, and anti-cancer treatment from July 2014 - June 2018. Patients were followed from date of metastasis and stratified by LoT and prior and current exposure to PD(L)1i. Mean total medical costs included all Medicare-covered Parts A/B costs. On treatment medical costs during each LoT were reported per patient per month (PPPM) and were categorized as anti-cancer drug costs or medical management costs (excluding anti-cancer drugs). Results: 438 beneficiaries met inclusion criteria: median age 75 years, 54% female, 91% white, 116 with G12C mutations. 1L patients receiving PD(L)1i had higher total medical costs ($14,331) than those not receiving PD(L)1i ($10,055). Total medical cost of care was similar between patients on 1L ($12,178) and 2L/3L ($12,042). Although total cost of care was similar among 2L/3L patients, irrespective of PD(L)1i exposure status, the medical management costs in patients who progressed after a PD(L)1i or had never received a PD(L)1i were almost twice the medical management costs of the PD(L)1i treated patients. Conclusions: This study demonstrates a high economic burden exists among Medicare patients with KRAS-mutated mNSCLC who have progressed after 1L therapy and for whom there are no targeted treatment options available. [Table: see text]
Quality of End-of-Life Care for Medicare Advantage Enrollees—Does It Measure Up?
Authors: Momotazur Rahman, David J. Meyers, Pedro Gozalo
Journal: JAMA Network Open (2020)

Claire K. Ankuda, MD, MPH; Amy S. Kelley, MD, MS; R. Sean Morrison, MD; Vicki A. Freedman, PhD; Joan M. Teno, MD, MS
AlphaBeta: computational inference of epimutation rates and spectra from high-throughput DNA methylation data in plants
Authors: Yadollah Shahryary, Aikaterini Symeonidi, Rashmi R. Hazarika, Johanna Denkena, Talha Mubeen, Brigitte Hofmeister, Thomas van Gurp, Maria Colomé-Tatché, Koen J.F. Verhoeven, Gerald Tuskan, Robert J. Schmitz, Frank Johannes
Journal: Genome biology (2020)

Abstract Stochastic changes in DNA methylation (i.e., spontaneous epimutations) contribute to methylome diversity in plants. Here, we describe AlphaBeta , a computational method for estimating the precise rate of such stochastic events using pedigree-based DNA methylation data as input. We demonstrate how AlphaBeta can be employed to study transgenerationally heritable epimutations in clonal or sexually derived mutation accumulation lines, as well as somatic epimutations in long-lived perennials. Application of our method to published and new data reveals that spontaneous epimutations accumulate neutrally at the genome-wide scale, originate mainly during somatic development and that they can be used as a molecular clock for age-dating trees.
Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19
Authors: Matthew C. Woodruff, Richard P. Ramonell, Doan C. Nguyen, Kevin S. Cashman, Ankur Singh Saini, Natalie S. Haddad, Ariel M. Ley, Shuya Kyu, J. Christina Howell, Tugba Ozturk, Saeyun Lee, Naveenchandra Suryadevara, James Brett Case, Regina Bugrovsky, Weirong Chen, Jacob Estrada, Andrea Morrison-Porter, Andrew Derrico, Fabliha A. Anam, Monika Sharma, Henry M. Wu, Sang N. Le, Scott A. Jenks, Christopher M. Tipton, Bashar Staitieh, John L. Daiss, Eliver Ghosn, Michael S. Diamond, Robert H. Carnahan, James E. Crowe, William T. Hu, F. Eun-Hyung Lee, Ignacio Sanz
Journal: Nature Immunology (2020)

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling. Sanz and colleagues examine B cell subsets in a cohort of patients with COVID-19. Severely ill patients have higher frequencies of activated extrafollicular T-bet+ B cells that form antibody-secreting cells, the majority of which express germline sequences and are reminiscent of antibody responses observed in patients with systemic lupus erythematosus during flares.
Concerning P450 Evolution: Structural Analyses Support Bacterial Origin of Sterol 14α-Demethylases
Authors: David C Lamb, Tatiana Y Hargrove, Bin Zhao, Zdzislaw Wawrzak, Jared V Goldstone, William David Nes, Steven L Kelly, Michael R Waterman, John J Stegeman, Galina I Lepesheva
Journal: Molecular Biology and Evolution (2020)

Sterol biosynthesis, primarily associated with eukaryotic kingdoms of life, occurs as an abbreviated pathway in the bacterium Methylococcus capsulatus. Sterol 14α-demethylation is an essential step in this pathway and is catalyzed by cytochrome P450 51 (CYP51). In M. capsulatus, the enzyme consists of the P450 domain naturally fused to a ferredoxin domain at the C-terminus (CYP51fx). The structure of M. capsulatus CYP51fx was solved to 2.7 Å resolution and is the first structure of a bacterial sterol biosynthetic enzyme. The structure contained one P450 molecule per asymmetric unit with no electron density seen for ferredoxin. We connect this with the requirement of P450 substrate binding in order to activate productive ferredoxin binding. Further, the structure of the P450 domain with bound detergent (which replaced the substrate upon crystallization) was solved to 2.4 Å resolution. Comparison of these two structures to the CYP51s from human, fungi, and protozoa reveals strict conservation of the overall protein architecture. However, the structure of an "orphan" P450 from nonsterol-producing Mycobacterium tuberculosis that also has CYP51 activity reveals marked differences, suggesting that loss of function in vivo might have led to alterations in the structural constraints. Our results are consistent with the idea that eukaryotic and bacterial CYP51s evolved from a common cenancestor and that early eukaryotes may have recruited CYP51 from a bacterial source. The idea is supported by bioinformatic analysis, revealing the presence of CYP51 genes in >1,000 bacteria from nine different phyla, >50 of them being natural CYP51fx fusion proteins.
Epidemiological parameters of COVID-19 and its implication for infectivity among patients in China, 1 January to 11 February 2020
Authors: Qing-Bin Lu, Yong Zhang, Ming-Jin Liu, Hai-Yang Zhang, Neda Jalali, An-Ran Zhang, Jia-Chen Li, Han Zhao, Qian-Qian Song, Tian-Shuo Zhao, Jing Zhao, Han-Yu Liu, Juan Du, Ai-Ying Teng, Zi-Wei Zhou, Shi-Xia Zhou, Tian-Le Che, Tao Wang, Tong Yang, Xiu-Gang Guan, Xue-Fang Peng, Yu-Na Wang, Yuan-Yuan Zhang, Shou-Ming Lv, Bao-Cheng Liu, Wen-Qiang Shi, Xiao-Ai Zhang, Xiao-Gang Duan, Wei Liu, Yang Yang, Li-Qun Fang
Journal: Eurosurveillance (2020)

Background The natural history of disease in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained obscure during the early pandemic. Aim Our objective was to estimate epidemiological parameters of coronavirus disease (COVID-19) and assess the relative infectivity of the incubation period. Methods We estimated the distributions of four epidemiological parameters of SARS-CoV-2 transmission using a large database of COVID-19 cases and potential transmission pairs of cases, and assessed their heterogeneity by demographics, epidemic phase and geographical region. We further calculated the time of peak infectivity and quantified the proportion of secondary infections during the incubation period. Results The median incubation period was 7.2 (95% confidence interval (CI): 6.9‒7.5) days. The median serial and generation intervals were similar, 4.7 (95% CI: 4.2‒5.3) and 4.6 (95% CI: 4.2‒5.1) days, respectively. Paediatric cases &lt; 18 years had a longer incubation period than adult age groups (p = 0.007). The median incubation period increased from 4.4 days before 25 January to 11.5 days after 31 January (p &lt; 0.001), whereas the median serial (generation) interval contracted from 5.9 (4.8) days before 25 January to 3.4 (3.7) days after. The median time from symptom onset to discharge was also shortened from 18.3 before 22 January to 14.1 days after. Peak infectivity occurred 1 day before symptom onset on average, and the incubation period accounted for 70% of transmission. Conclusion The high infectivity during the incubation period led to short generation and serial intervals, necessitating aggressive control measures such as early case finding and quarantine of close contacts.
Barriers to implementation of virtual collection of patient-reported data in the COVID-19 era
Authors: Karineh Kazazian, Wendy Johnston, Jessica Bogach, Carol J. Swallow
Journal: Clinical Cancer Research (2020)

Introduction: A marked shift in ambulatory patient assessment was instituted by cancer centers in response to theCOVID-19 crisis  At our center, non-urgent appointments were deferred, and essential assessments were conductedvirtually whenever possible  Prior to COVID-19, all patients attending ambulatory clinic completed an EdmontonSymptom Assessment Scale (ESAS) form via touch pad, with assistance as needed by clinic volunteers  Ourpurpose here was to explore how virtual conduct of clinics impacted the collection of patient-reported outcomes andto address the unmet need for recognition and management of severe symptoms, particularly depression/anxiety  Methods: We performed a mixed methods cross-sectional study to test the feasibility of remote completion of theESAS form by patients scheduled for appointments at a weekly surgical oncology clinic at a major Canadian cancercenter  Over the course of the first 5 weeks of the study, patients were phoned after their appointment to requestpermission to email the ESAS form and asked to return the completed form electronically  Over the next 2 weeks, patients who attended in-person appointments were asked to complete a hard-copy ESAS form in clinic  Clinicallysignificant distress was defined a priori as score >2 for depression and >3 for anxiety  We compared compliance with the two methods (virtual vs  hard-copy) of patient-reported data collection  Results: For the entire study cohort, median age was 64 (35-89) and 48% were female  For the virtual method ofESAS completion, 45 patients had telephone contact attempted: 30 agreed to study participation, 1 declined, and 14could not be reached despite repeated attempts  For the hard-copy method, all 22 patients approached consentedto participation  For the virtual method, 15 patients successfully completed and returned the ESAS formelectronically, yielding an overall compliance rate of 33%  For the hard-copy method, the compliance rate was 95%(1 patient deferred after consenting, then did not return the form)  There were no differences in patient age, gender, or tumor type between the two methods  For the patients who agreed to the virtual method but did not return acompleted electronic form, the following barriers were identified: unable to open/complete PDF;technology phobia;lack of motivation;patient provided invalid email address  Of the completed forms, 28% revealed a depression score>2 and 31% an anxiety score >3;22% reported both severe depression and anxiety  There was no difference in thedegree of distress reported virtually or via hard copy
Fusion peptide engineered “statically-versatile” titanium implant simultaneously enhancing anti-infection, vascularization and osseointegration
Authors: Junjian Chen, Guansong Hu, Tianjie Li, Yunhua Chen, Meng Gao, Qingtao Li, Lijing Hao, Yongguang Jia, Lin Wang, Yingjun Wang
Journal: Biomaterials (2020)