tbuckley/cabot-search huggingface dataset:
Evolving impact of long-term survival results on metastatic melanoma treatment
Authors: Olivier Michielin, Michael B Atkins, Henry B Koon, Reinhard Dummer, Paolo Antonio Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2020)

Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.
Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM
Authors: Thuja Meurer, Pietro Crivello, Maximilian Metzing, Michel Kester, Dominik A. Megger, Weiqiang Chen, Peter A. van Veelen, Peter van Balen, Astrid M. Westendorf, Georg Homa, Sophia E. Layer, Amin T. Turki, Marieke Griffioen, Peter A. Horn, Barbara Sitek, Dietrich W. Beelen, J. H. Frederik Falkenburg, Esteban Arrieta-Bolaños, Katharina Fleischhauer
Journal: Blood (2020)
Political interference in public health science during covid-19
Authors: Gregg Gonsalves, Gavin Yamey
Journal: BMJ (2020)

<h3>Introduction</h3> When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses. <h3>Methods and analysis</h3> Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses. <h3>Ethics and dissemination</h3> This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication. <h3>Protocol registration</h3> In PROSPERO CRD42013006702, 11. December 2013.
Targeting rehabilitation to improve outcomes after total knee arthroplasty in patients at risk of poor outcomes: randomised controlled trial
Authors: David F Hamilton, David J Beard, Karen L Barker, Gary J Macfarlane, Christopher E Tuck, Andrew Stoddart, Timothy Wilton, James D Hutchinson, Gordon D Murray, A Hamish R W Simpson
Journal: BMJ (2020)

Abstract Objective To evaluate whether a progressive course of outpatient physiotherapy offers superior outcomes to a single physiotherapy review and home exercise based intervention when targeted at patients with a predicted poor outcome after total knee arthroplasty. Design Parallel group randomised controlled trial. Setting 13 secondary and tertiary care centres in the UK providing postoperative physiotherapy. Participants 334 participants with knee osteoarthritis who were defined as at risk of a poor outcome after total knee arthroplasty, based on the Oxford knee score, at six weeks postoperatively. 163 were allocated to therapist led outpatient rehabilitation and 171 to a home exercise based protocol. Interventions All participants were reviewed by a physiotherapist and commenced 18 sessions of rehabilitation over six weeks, either as therapist led outpatient rehabilitation (progressive goal oriented functional rehabilitation protocol, modified weekly in one-one contact sessions) or as physiotherapy review followed by a home exercise based regimen (without progressive input from a physiotherapist). Main outcome measures Primary outcome was Oxford knee score at 52 weeks, with a 4 point difference between groups considered to be clinically meaningful. Secondary outcomes included additional patient reported outcome measures of pain and function at 14, 26, and 52 weeks post-surgery. Results 334 patients were randomised. Eight were lost to follow-up. Intervention compliance was more than 85%. The between group difference in Oxford knee score at 52 weeks was 1.91 (95% confidence interval −0.18 to 3.99) points, favouring the outpatient rehabilitation arm (P=0.07). When all time point data were analysed, the between group difference in Oxford knee score was a non-clinically meaningful 2.25 points (0.61 to 3.90, P=0.01). No between group differences were found for secondary outcomes of average pain (0.25 points, −0.78 to 0.28, P=0.36) or worst pain (0.22 points, −0.71 to 0.41, P=0.50) at 52 weeks or earlier time points, or of satisfaction with outcome (odds ratio 1.07, 95% confidence interval 0.71 to 1.62, P=0.75) or post-intervention function (4.64 seconds, 95% confidence interval −14.25 to 4.96, P=0.34). Conclusions Outpatient therapist led rehabilitation was not superior to a single physiotherapist review and home exercise based regimen in patients at risk of poor outcomes after total knee arthroplasty. No clinically relevant differences were observed across primary or secondary outcome measures. Trials registration Current Controlled Trials ISRCTN23357609 and ClinicalTrials.gov NCT01849445 .
Patient self-reported awareness of COVID: Overconfidence in knowledge, underestimation of risk.
Authors: Ruth Kieran, carolyn moloney, John Kennedy, Maeve Aine Lowery, Cliona Grant, David James Gallagher, Dearbhaile M. O'Donnell, Fergal Kelleher, Sue Sukor, Michael Thomas McCarthy, Sinead Cuffe
Journal: Journal of Clinical Oncology (2020)

174 Background: Oncology patients have had to adapt to minimize the risks of contracting COVID-19. We assessed patient knowledge of COVID, and the impact of the pandemic on their behaviours, concerns and healthcare experience, to identify any further education/quality improvement needs. Methods: Following ethical approval, a 16 page survey was distributed to 120 oncology patients attending the day unit of a tertiary Irish cancer center for systemic anti-cancer therapy (May/June 2020). The Irish COVID rate during this period was 33.8 new cases/day (pop. 4.9 million). Results: 101 responses were received. Cancer types included breast (19%), gastrointestinal (29%), head and neck (11%), and lung (13%). 31% had been tested for COVID; just 1 patient was positive. 100% were aware of advice to “cocoon” and reported good understanding of this. 75% reported complete compliance, but of those, 73% were not social-distancing within their homes, 22% received visitors, and 36% continued to shop in-store; of these, 42% shopped as/more often than pre-COVID. Of the 51 patients regularly shopping, many were not using risk-reduction strategies e.g. social distancing (22%), mask-wearing (20%), using “priority shopping’ hours (31%), avoiding public transport (26%). 94% felt confident/very confident in recognizing COVID symptoms, but 66% did not recognize two or more key symptoms from a list of 10, most frequently aches/pains (58%), fatigue (55%), altered smell/taste (33%) and dyspnea (14%). The number recognized did not correlate with confidence (p = 0.9) or desire for more information about COVID (p = 0.9). 40% did not feel they were at higher risk of contracting COVID, while 15% thought they were no more likely to be very sick than an average person if infected. Many did not know that chemotherapy, steroids, radiation, and immunotherapy can impact morbidity/mortality in COVID (31%, 70%, 44% and 49% respectively). 46% were somewhat/very fearful of COVID, but this did not strongly predict for either protective (e.g. mask-wearing: OR 1.1, 95% CI 0.3-4.8 p = 0.9), or risk behaviors (e.g. continuing to shop frequently: OR 0.5, 95% CI 0.1-1.4 p = 0.2). 66% would like more cancer specific information, particularly about prevention (45%) and symptoms (33%), with a preference for written information (74%). Conclusions: Despite self-reported confidence in knowledge, patient’s self-assessments of their risk category and the preventative strategies they should use may be inaccurate. Increased education about risk, cocooning and symptom recognition is necessary.
Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis
Authors: Hanxue Zheng, Zhi Yang, Zhenlong Xin, Yang Yang, Yuan Yu, Jihong Cui, Hongbo Liu, Fulin Chen
Journal: Theranostics (2020)

Fibrosis exists in almost all organs/tissues of the human body, plays an important role in the occurrence and development of diseases and is also a hallmark of the aging process. However, there is no effective prevention or therapeutic method for fibrogenesis. As a serine/threonine (Ser/Thr)-protein kinase, glycogen synthase kinase-3β (GSK-3β) is a vital signaling mediator that participates in a variety of biological events and can inhibit extracellular matrix (ECM) accumulation and the epithelial-mesenchymal transition (EMT) process, thereby exerting its protective role against the fibrosis of various organs/tissues, including the heart, lung, liver, and kidney. Moreover, we further present the upstream regulators and downstream effectors of the GSK-3β pathway during fibrosis and comprehensively summarize the roles of GSK-3β in the regulation of fibrosis and provide several potential targets for research. Collectively, the information reviewed here highlights recent advances vital for experimental research and clinical development, illuminating the possibility of GSK-3β as a novel therapeutic target for the management of tissue fibrosis in the future.
Abstract 11479: Discordance Between Electrocardiograph Rhythm and Atrial Appendage Doppler Wave Form Phenotype Predicts Post Cardiac Surgery Atrial Fibrillation: A Prospective Intraoperative Study
Authors: Qizhe Cai, Akiva Nachshon, Jason D Matos, Feroze Mahmood, Adam Lerner, John Mitchell, Ariel Mueller, Warren J Manning
Journal: Circulation (2019)

Introduction: Post-operative atrial fibrillation (POAF) after cardiac surgery is associated with increased length of stay and long-term risk of stroke. Identification of at-risk patients is therefo...
FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome
Authors: Michael Schieber, Christian Marinaccio, Lyndsey C. Bolanos, Wendy D. Haffey, Kenneth D. Greis, Daniel T. Starczynowski, John D. Crispino
Journal: Blood Cancer Journal (2020)

Abstract Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
Prime editing efficiently generates W542L and S621I double mutations in two ALS genes in maize
Authors: Yuan-Yuan Jiang, Yi-Ping Chai, Min-Hui Lu, Xiu-Li Han, Qiupeng Lin, Yu Zhang, Qiang Zhang, Yun Zhou, Xue-Chen Wang, Caixia Gao, Qi-Jun Chen
Journal: Genome biology (2020)

Prime editing is a novel and universal CRISPR/Cas-derived precision genome-editing technology that has been recently developed. However, low efficiency of prime editing has been shown in transgenic rice lines. We hypothesize that enhancing pegRNA expression could improve prime-editing efficiency. In this report, we describe two strategies for enhancing pegRNA expression. We construct a prime editing vector harboring two pegRNA variants for W542L and S621I double mutations in ZmALS1 and ZmALS2. Compared with previous reports in rice, we achieve much higher prime-editing efficiency in maize. Our results are inspiring and provide a direction for the optimization of plant prime editors.
Impact of a built-in electronic medical record prompt on guideline-recommended prophylactic antiviral usage in patients with multiple myeloma receiving proteasome inhibitors.
Authors: Garrett Young, Stacey McCullough, George Arrowsmith, Aaron J. Lyss, Stephen Matthew Schleicher, Natalie R. Dickson, Edward Arrowsmith
Journal: Journal of Clinical Oncology (2020)

248 Background: Guidelines support the use of prophylactic antivirals to prevent reactivation of herpes varicella in patients with multiple myeloma (MM) on proteasome inhibitors (PI). In our network of five oncology practices spanning over 100 clinic sites, one practice has a built-in prompt for acyclovir use in patients receiving a PI, while the other four practices do not. We used this natural experiment to determine the impact of this prompt on appropriate prophylactic antiviral usage in this patient population. Methods: We retrospectively identified all patients in our network with MM beginning a regimen containing a PI between 1/1/19 and 5/28/20. Of these patients, we identified those with documentation of a prescription for acyclovir or valacyclovir before or within 2 days of the first PI dose. We compared prophylactic usage across five practices. Practice 1 had built a prompt for the prescription of acyclovir in regimens containing bortezomib or carfilzomib within the electronic medical record (EMR) which both reminded physicians and nurses and simplified the prescribing process. No other practices had similar EMR prompts. Results: We identified 583 patients with MM who received a PI during the study period. Wide variation in rates of prophylactic antiviral usage existed across the five practices (range 21%-94%). The highest rate of prophylactic antiviral usage was practice 1 (94%). This was the only practice with a built-in EMR prompt for acyclovir usage in PI regimens. We found no association between use of prophylactic antivirals and individual provider-level volume of patients with MM. Conclusions: Use of prophylactic therapy is heterogeneous across practices. A comprehensive treatment plan containing a prompt in the EMR can markedly increase appropriate utilization. We plan to add an EMR prompt and analytics-driven reminders across our network to improve utilization of all guideline-recommend, orally administered prophylactic medications. [Table: see text]
Association between prehospital time and outcome of trauma patients in 4 Asian countries: A cross-national, multicenter cohort study
Authors: Chi-Hsin Chen, Sang Do Shin, Jen-Tang Sun, Sabariah Faizah Jamaluddin, Hideharu Tanaka, Kyoung Jun Song, Kentaro Kajino, Akio Kimura, Edward Pei-Chuan Huang, Ming-Ju Hsieh, Matthew Huei-Ming Ma, Wen-Chu Chiang
Journal: PLoS Medicine (2020)

Background Whether rapid transportation can benefit patients with trauma remains controversial. We determined the association between prehospital time and outcome to explore the concept of the "golden hour" for injured patients. Methods and findings We conducted a retrospective cohort study of trauma patients transported from the scene to hospitals by emergency medical service (EMS) from January 1, 2016, to November 30, 2018, using data from the Pan-Asia Trauma Outcomes Study (PATOS) database. Prehospital time intervals were categorized into response time (RT), scene to hospital time (SH), and total prehospital time (TPT). The outcomes were 30-day mortality and functional status at hospital discharge. Multivariable logistic regression was used to investigate the association of prehospital time and outcomes to adjust for factors including age, sex, mechanism and type of injury, Injury Severity Score (ISS), Revised Trauma Score (RTS), and prehospital interventions. Overall, 24,365 patients from 4 countries (645 patients from Japan, 16,476 patients from Korea, 5,358 patients from Malaysia, and 1,886 patients from Taiwan) were included in the analysis. Among included patients, the median age was 45 years (lower quartile [Q1]–upper quartile [Q3]: 25–62), and 15,498 (63.6%) patients were male. Median (Q1–Q3) RT, SH, and TPT were 20 (Q1–Q3: 12–39), 21 (Q1–Q3: 16–29), and 47 (Q1–Q3: 32–60) minutes, respectively. In all, 280 patients (1.1%) died within 30 days after injury. Prehospital time intervals were not associated with 30-day mortality. The adjusted odds ratios (aORs) per 10 minutes of RT, SH, and TPT were 0.99 (95% CI 0.92–1.06, p = 0.740), 1.08 (95% CI 1.00–1.17, p = 0.065), and 1.03 (95% CI 0.98–1.09, p = 0.236), respectively. However, long prehospital time was detrimental to functional survival. The aORs of RT, SH, and TPT per 10-minute delay were 1.06 (95% CI 1.04–1.08, p < 0.001), 1.05 (95% CI 1.01–1.08, p = 0.007), and 1.06 (95% CI 1.04–1.08, p < 0.001), respectively. The key limitation of our study is the missing data inherent to the retrospective design. Another major limitation is the aggregate nature of the data from different countries and unaccounted confounders such as in-hospital management. Conclusions Longer prehospital time was not associated with an increased risk of 30-day mortality, but it may be associated with increased risk of poor functional outcomes in injured patients. This finding supports the concept of the "golden hour" for trauma patients during prehospital care in the countries studied.
Right Atrial Pacing to Improve Acute Hemodynamics in Pulmonary Arterial Hypertension
Authors: Jasjeet S. Khural, Brian A. Houston, Peter J. Leary, Stephen C. Mathai, Todd M. Kolb, Rachel Damico, Paul M. Hassoun, David A. Kass, Steven Hsu, Ryan J. Tedford
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
SRMS correlated with immune infiltration and lung cancer: Allusion for COVID-19
Authors: Beesetti Swarna, Yong-Dong Wang, Malia B. Potts
Journal: Clinical Cancer Research (2020)

Background: The non-receptor tyrosine kinase, SRMS (Src-related kinase lacking C-terminal regulatory tyrosineand N-terminal myristoylation sites) is a member of the BRK family kinases (BFKs) that represents an evolutionarilyconserved relative of the Src family kinases (SFKs) and is shown to restrain autophagy in mammalian cells  Geneenrichment analyses using the Ingenuity Pathway analyses (IPA) of SRMS interacting partners predicted viralinfection as a significantly increased cellular processes  However, the correlation between SRMS and prognosis inLUAD (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma) or its impact on COVID-19 isunderstudied  Methods: We analyzed the expression levels of SRMS, and the correlation between SRMS and immune infiltrationlevel in LUAD and LUSC was investigated using TIMER database  Open Target platform was used to analyze theassociation of SRMS with disease  In addition, we used GSE30589 databases to elucidate the changes of SRMSexpression in vitro after SARS-CoV infection in Vero E6 and MA-104 cells  Results: SRMS was elevated in LUAD and LUSC compared to normal tissues  The expression of SRMS wasnegatively correlated with the level of immune infiltration of CD8+T cells in LUAD and LUSC  We found that theexpression of SRMS increased in vitro after SARS-CoV infection in Vero E6 and MA-104 cells  Conclusion: SRMS expression increased significantly in LUAD and LUSC, and this elevated SRMS was negativelycorrelated with immune infiltration at tumors  SARS-CoV infection increased the SRMS expression  This suggeststhat patients with LUAD and LUSC may be more susceptible to SARS-CoV-2 due to increased SRMS levels thatinhibit autophagy and alter tumor microenvironment correlated with reduced immune infiltration, which in turn mayworsen the prognoses of LUAD and LUSC patients after SARS-CoV-2 infection
Management of hypertriglyceridemia
Authors: Vinaya Simha
Journal: BMJ (2020)

Abstract Hypertriglyceridemia is one of the most common lipid abnormalities encountered in clinical practice. Many monogenic disorders causing severe hypertriglyceridemia have been identified, but in most patients triglyceride elevations result from a combination of multiple genetic variations with small effects and environmental factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol misuse, and various commonly used drugs. Correcting these factors and optimizing lifestyle choices, including dietary modification, is important before starting drug treatment. The goal of drug treatment is to reduce the risk of pancreatitis in patients with severe hypertriglyceridemia and cardiovascular disease in those with moderate hypertriglyceridemia. This review discusses the various genetic and acquired causes of hypertriglyceridemia, as well as current management strategies. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented.
What have we learned ventilating COVID-19 patients?
Authors: Uriel Trahtemberg, Arthur S. Slutsky, Jesús Villar
Journal: Intensive Care Medicine (2020)

The spectrum of coronavirus disease 19 ranges from asymptomatic to mild respiratory disease, pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death.About 5% of COVID-19 patients require ICU admission and ~ 3.5% develop ARDS, although this number depends on reporting bias, practice patterns, and resource availability.In this Editorial, we present a viewpoint on the ventilatory management of COVID-19-induced ARDS, based on the underlying pathophysiology.Our message is simple: after almost a year of treating ARDS caused by COVID-19, everything-and nothing-has changed [1].