tbuckley/cabot-search huggingface dataset:
US task force recommends extending lung cancer screenings to over 50s
Authors: Owen Dyer
Journal: BMJ (2021)

The US Preventive Services Task Force (USPSTF), the government’s influential guidelines panel, has updated its recommendations on lung cancer screening, broadening eligibility to include younger and lighter smokers.1

The USPSTF now recommends that people aged 50 or over who have a smoking history of at least 20 pack years (a pack a day for 20 years or two packs a day for 10) should be offered an annual scan using low dose computed tomography (LDCT).

The previous guidelines, dating from 2013, recommended screening people aged over 55 with at least 30 pack years of smoking history.

The new guidelines continue to recommend against screening people who quit smoking at least 15 years ago, and those who cannot benefit from early detection because they are unwilling or unable to undergo surgical resection of a detected tumour. …
Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies
Authors: Melanie Decker, Tim Lammens, Alina Ferster, Miriam Erlacher, Ayami Yoshimi, Charlotte M. Niemeyer, Martijn P. T. Ernst, Marc H. G. P. Raaijmakers, Nicolas Duployez, Andreas Flaum, Doris Steinemann, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger
Journal: Leukemia (2021)
Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC
Authors: Petra Ross-Macdonald, Alice M Walsh, Scott D Chasalow, Ron Ammar, Simon Papillon-Cavanagh, Peter M Szabo, Toni K Choueiri, Mario Sznol, Megan Wind-Rotolo
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Nivolumab is an immune checkpoint inhibitor targeting the programmed death-1 receptor that improves survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). In contrast to other tumor types that respond to immunotherapy, factors such as programmed death ligand-1 (PD-L1) status and tumor mutational burden show limited predictive utility in ccRCC. To address this gap, we report here the first molecular characterization of nivolumab response using paired index lesions, before and during treatment of metastatic ccRCC. Methods We analyzed gene expression and T-cell receptor (TCR) clonality using lesion-paired biopsies provided in the CheckMate 009 trial and integrated the results with their PD-L1/CD4/CD8 status, genomic mutation status and serum cytokine assays. Statistical tests included linear mixed models, logistic regression models, Fisher’s exact test, and Kruskal-Wallis rank-sum test. Results We identified transcripts related to response, both at baseline and on therapy, including several that are amenable to peripheral bioassays or to therapeutic intervention. At both timepoints, response was positively associated with T-cell infiltration but not associated with TCR clonality, and some non-Responders were highly infiltrated. Lower baseline T-cell infiltration correlated with elevated transcription of Wnt/β-catenin signaling components and hypoxia-regulated genes, including the Treg chemoattractant CCL28. On treatment, analysis of the non-responding patients whose tumors were highly T-cell infiltrated suggests association of the RIG-I-MDA5 pathway in their nivolumab resistance. We also analyzed our data using previous transcriptional classifications of ccRCC and found they concordantly identified a molecular subtype that has enhanced nivolumab response but is sunitinib-resistant. Conclusion Our study describes molecular characteristics of response and resistance to nivolumab in patients with metastatic ccRCC, potentially impacting patient selection and first-line treatment decisions. Trial registration number NCT01358721 .
Pathogenesis, MicroRNA‐122 Gene‐Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection
Authors: Joy E. Tomlinson, Raphael Wolfisberg, Ulrik Fahnøe, Roosheel S. Patel, Sheetal Trivedi, Arvind Kumar, Himanshu Sharma, Louise Nielsen, Sean P. McDonough, Jens Bukh, Bud C. Tennant, Amit Kapoor, Brad R. Rosenberg, Charles M. Rice, Thomas J. Divers, Gerlinde R. Van de Walle, Troels K.H. Scheel
Journal: Hepatology (2021)

Equine hepacivirus (EqHV) is phylogenetically the closest relative of HCV and shares genome organization, hepatotropism, transient or persistent infection outcome, and the ability to cause hepatitis. Thus, EqHV studies are important to understand equine liver disease and further as an outbred surrogate animal model for HCV pathogenesis and protective immune responses. Here, we aimed to characterize the course of EqHV infection and associated protective immune responses.Seven horses were experimentally inoculated with EqHV, monitored for 6 months, and rechallenged with the same and, subsequently, a heterologous EqHV. Clearance was the primary outcome (6 of 7) and was associated with subclinical hepatitis characterized by lymphocytic infiltrate and individual hepatocyte necrosis. Seroconversion was delayed and antibody titers waned slowly. Clearance of primary infection conferred nonsterilizing immunity, resulting in shortened duration of viremia after rechallenge. Peripheral blood mononuclear cell responses in horses were minimal, although EqHV-specific T cells were identified. Additionally, an interferon-stimulated gene signature was detected in the liver during EqHV infection, similar to acute HCV in humans. EqHV, as HCV, is stimulated by direct binding of the liver-specific microRNA (miR), miR-122. Interestingly, we found that EqHV infection sequesters enough miR-122 to functionally affect gene regulation in the liver. This RNA-based mechanism thus could have consequences for pathology.EqHV infection in horses typically has an acute resolving course, and the protective immune response lasts for at least a year and broadly attenuates subsequent infections. This could have important implications to achieve the primary goal of an HCV vaccine; to prevent chronicity while accepting acute resolving infection after virus exposure.
Identification of tumor antigens and immune subtypes of pancreatic adenocarcinoma for mRNA vaccine development
Authors: Xing Huang, Gang Zhang, Tianyu Tang, Tingbo Liang
Journal: Molecular Cancer (2021)

Although mRNA vaccines have been effective against multiple cancers, their efficacy against pancreatic adenocarcinoma (PAAD) remains undefined. Accumulating evidence suggests that immunotyping can indicate the comprehensive immune status in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potent antigens in PAAD for mRNA vaccine development, and further distinguish immune subtypes of PAAD to construct an immune landscape for selecting suitable patients for vaccination.Gene expression profiles and clinical information of 239 PAAD datasets were extracted from ICGC, and RNA-Seq data of 103 samples were retrieved from TCGA. GEPIA was used to calculate differential expression levels and prognostic indices, cBioPortal program was used to compare genetic alterations, and TIMER was used to explore correlation between genes and immune infiltrating cells. Consensus cluster was used for consistency matrix construction and data clustering, DAVID was used for functional annotation, and graph learning-based dimensional reduction was used to depict immune landscape.Six overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in PAAD, including ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A. Furthermore, five immune subtypes (IS1-IS5) and nine immune gene modules of PAAD were identified that were consistent in both patient cohorts. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to the other subtypes. IS4 and IS5 tumors were immunologically cold and associated with higher tumor mutation burden. Immunogenic cell death modulators, immune checkpoints, and CA125 and CA199, were also differentially expressed among the five immune subtypes. Finally, the immune landscape of PAAD showed a high degree of heterogeneity between individual patients.ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A are potent antigens for developing anti-PAAD mRNA vaccine, and patients with IS4 and IS5 tumors are suitable for vaccination.
無視可能な副作用を有する増強抗癌作用のための環状アセタール結合によるゲムシタビンの高分子修飾【JST・京大機械翻訳】
Authors: Takemoto Hiroyasu, Inaba Takanori, Nomoto Takahiro, Matsui Makoto, Liu Xiaomeng, Toyoda Masahiro, Honda Yuto, Taniwaki Kaori, Yamada Naoki, Kim Junhyun, Tomoda Keishiro, Nishiyama Nobuhiro
Journal: Biomaterials (2020)
Survival estimates in European cystic fibrosis patients and the impact of socioeconomic factors: a retrospective registry cohort study
Authors: Edward F. McKone, Cono Ariti, Abaigeal Jackson, Anna Zolin, Siobhán B. Carr, Annalisa Orenti, Jacqui G. van Rens, Lydie Lemonnier, Milan Macek, Ruth H. Keogh, Lutz Naehrlich
Journal: European Respiratory Journal (2021)

Background Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined. Methods CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan–Meier method. Differences in the survival curves were assessed using the log-rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CF transmembrane conductance regulator ( CFTR ) genotype and transplant status. Results The final analysis included 13 countries with 31 987 subjects (135 833 person-years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 (95% CI 50.0–53.4) years. After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (p&lt;0.001). Countries in the highest third of healthcare spending had a 46% lower hazard of mortality (HR 0.54, 95% CI 0.45–0.64) than countries in the lowest third of healthcare spending. Conclusions Median survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors.
Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection
Authors: Nina Le Bert, Hannah E. Clapham, Anthony T. Tan, Wan Ni Chia, Christine Y.L. Tham, Jane M. Lim, Kamini Kunasegaran, Linda Wei Lin Tan, Charles-Antoine Dutertre, Nivedita Shankar, Joey M.E. Lim, Louisa Jin Sun, Marina Zahari, Zaw Myo Tun, Vishakha Kumar, Beng Lee Lim, Siew Hoon Lim, Adeline Chia, Yee-Joo Tan, Paul Anantharajah Tambyah, Shirin Kalimuddin, David Lye, Jenny G.H. Low, Lin-Fa Wang, Wei Yee Wan, Li Yang Hsu, Antonio Bertoletti, Clarence C. Tam
Journal: The Journal of Experimental Medicine (2021)

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2–specific T cells in individuals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2–specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2–specific T cells were similar between asymptomatic and symptomatic individuals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2–specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2–infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.
9P Predictive factors and profiles of tumour response to epigenetic drugs in phase I trials
Authors: A. Procureur, A. Bizot, J-M. Michot, S. Ammari, L. Verlingue, C. Baldini, P. Martin-Romano, V. Ribrag, J-C. Soria, C. Massard, S. Postel-Vinay
Journal: Annals of Oncology (2021)
Experiences of Latinx Individuals Hospitalized for COVID-19
Authors: Lilia Cervantes, Marlene Martin, Maria G. Frank, Julia F. Farfan, Mark Kearns, Luis A. Rubio, Allison Tong, Andrea Matus Gonzalez, Claudia Camacho, Adriana Collings, William Mundo, Neil R. Powe, Alicia Fernandez
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Latinx individuals, particularly immigrants, are at higher risk than non-Latinx White individuals of contracting and dying from coronavirus disease 2019 (COVID-19). Little is known about Latinx experiences with COVID-19 infection and treatment. <h3>Objective</h3> To describe the experiences of Latinx individuals who were hospitalized with and survived COVID-19. <h3>Design, Setting, and Participants</h3> The qualitative study used semistructured phone interviews of 60 Latinx adults who survived a COVID-19 hospitalization in public hospitals in San Francisco, California, and Denver, Colorado, from March 2020 to July 2020. Transcripts were analyzed using qualitative thematic analysis. Data analysis was conducted from May 2020 to September 2020. <h3>Main Outcomes and Measures</h3> Themes and subthemes that reflected patient experiences. <h3>Results</h3> Sixty people (24 women and 36 men; mean [SD] age, 48 [12] years) participated. All lived in low-income areas, 47 participants (78%) had more than 4 people in the home, and most (44 participants [73%]) were essential workers. Four participants (9%) could work from home, 12 (20%) had paid sick leave, and 21 (35%) lost their job because of COVID-19. We identified 5 themes (and subthemes) with public health and clinical care implications: COVID-19 was a distant and secondary threat (invincibility, misinformation and disbelief, ingrained social norms); COVID-19 was a compounder of disadvantage (fear of unemployment and eviction, lack of safeguards for undocumented immigrants, inability to protect self from COVID-19, and high-density housing); reluctance to seek medical care (worry about health care costs, concerned about ability to access care if uninsured or undocumented, undocumented immigrants fear deportation); health care system interactions (social isolation and change in hospital procedures, appreciation for clinicians and language access, and discharge with insufficient resources or clinical information); and faith and community resiliency (spirituality, Latinx COVID-19 advocates). <h3>Conclusions and Relevance</h3> In interviews, Latinx patients with COVID-19 who survived hospitalization described initial disease misinformation and economic and immigration fears as having driven exposure and delays in presentation. To confront COVID-19 as a compounder of social disadvantage, public health authorities should mitigate COVID-19–related misinformation, immigration fears, and challenges to health care access, as well as create policies that provide work protection and address economic disadvantages.
Classification of Comprehensive Neuro-Ophthalmologic Measures of Postacute Concussion
Authors: Christina N. Feller, May Goldenberg, Patrick D. Asselin, Kian Merchant-Borna, Beau Abar, Courtney Marie Cora Jones, Rebekah Mannix, Keisuke Kawata, Jeffrey J. Bazarian
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Symptom-based methods of concussion diagnosis in contact sports result in underdiagnosis and repeated head injury exposure, increasing the risk of long-term disability. Measures of neuro-ophthalmologic (NO) function have the potential to serve as objective aids, but their diagnostic utility is unknown. <h3>Objective</h3> To identify NO measures that accurately differentiate athletes with and without concussion. <h3>Design, Setting, and Participants</h3> This cohort study was conducted among athletes with and without concussion who were aged 17 to 22 years between 2016 and 2017. Eye movements and cognitive function were measured a median of 19 days after injury among patients who had an injury meeting the study definition of concussion while playing a sport (retrospectively selected from a concussion clinic), then compared with a control group of participants without concussion (enrolled from 104 noncontact collegiate athlete volunteers without prior head injury). Data analysis was conducted from November 2019 through May 2020. <h3>Exposure</h3> Concussion. <h3>Main Outcomes and Measures</h3> Classification accuracy of clinically important discriminator eye-tracking (ET) metrics. Participants' eye movements were evaluated with a 12-minute ET procedure, yielding 42 metrics related to smooth pursuit eye movement (SPEM), saccades, dynamic visual acuity, and reaction time. Clinically important discriminator metrics were defined as those with significantly different group differences and area under the receiver operator characteristic curves (AUROCs) of at least 0.70. <h3>Results</h3> A total of 34 participants with concussions (mean [SD] age, 19.7 [2.4] years; 20 [63%] men) and 54 participants without concussions (mean [SD] age, 20.8 [2.2] years; 31 [57%] men) completed the study. Six ET metrics (ie, simple reaction time, discriminate reaction time, discriminate visual reaction speed, choice visual reaction speed, and reaction time on 2 measures of dynamic visual acuity 2) were found to be clinically important; all were measures of reaction time, and none were related to SPEM. Combined, these 6 metrics had an AUROC of 0.90 (95% CI, 0.80-0.99), a sensitivity of 77.8%, and a specificity of 92.6%. The 6 metrics remained significant on sensitivity testing. <h3>Conclusions and Relevance</h3> In this study, ET measures of slowed visual reaction time had high classification accuracy for concussion. Accurate, objective measures of NO function have the potential to improve concussion recognition and reduce the disability associated with underdiagnosis.
Prospective Validation of an Electronic Health Record–Based, Real-Time Suicide Risk Model
Authors: Colin G. Walsh, Kevin B. Johnson, Michael Ripperger, Sarah Sperry, Joyce Harris, Nathaniel Clark, Elliot Fielstein, Laurie Novak, Katelyn Robinson, William W. Stead
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Numerous prognostic models of suicide risk have been published, but few have been implemented outside of integrated managed care systems. <h3>Objective</h3> To evaluate performance of a suicide attempt risk prediction model implemented in a vendor-supplied electronic health record to predict subsequent (1) suicidal ideation and (2) suicide attempt. <h3>Design, Setting, and Participants</h3> This observational cohort study evaluated implementation of a suicide attempt prediction model in live clinical systems without alerting. The cohort comprised patients seen for any reason in adult inpatient, emergency department, and ambulatory surgery settings at an academic medical center in the mid-South from June 2019 to April 2020. <h3>Main Outcomes and Measures</h3> Primary measures assessed external, prospective, and concurrent validity. Manual medical record validation of coded suicide attempts confirmed incident behaviors with intent to die. Subgroup analyses were performed based on demographic characteristics, relevant clinical context/setting, and presence or absence of universal screening. Performance was evaluated using discrimination (number needed to screen, C statistics, positive/negative predictive values) and calibration (Spiegelhalter<i>z</i>statistic). Recalibration was performed with logistic calibration. <h3>Results</h3> The system generated 115 905 predictions for 77 973 patients (42 490 [54%] men, 35 404 [45%] women, 60 586 [78%] White, 12 620 [16%] Black). Numbers needed to screen in highest risk quantiles were 23 and 271 for suicidal ideation and attempt, respectively. Performance was maintained across demographic subgroups. Numbers needed to screen for suicide attempt by sex were 256 for men and 323 for women; and by race: 373, 176, and 407 for White, Black, and non-White/non-Black patients, respectively. Model C statistics were, across the health system: 0.836 (95% CI, 0.836-0.837); adult hospital: 0.77 (95% CI, 0.77-0.772); emergency department: 0.778 (95% CI, 0.777-0.778); psychiatry inpatient settings: 0.634 (95% CI, 0.633-0.636). Predictions were initially miscalibrated (Spiegelhalter<i>z</i>= −3.1;<i>P</i>= .001) with improvement after recalibration (Spiegelhalter<i>z</i>= 1.1;<i>P</i>= .26). <h3>Conclusions and Relevance</h3> In this study, this real-time predictive model of suicide attempt risk showed reasonable numbers needed to screen in nonpsychiatric specialty settings in a large clinical system. Assuming that research-valid models will translate without performing this type of analysis risks inaccuracy in clinical practice, misclassification of risk, wasted effort, and missed opportunity to correct and prevent such problems. The next step is careful pairing with low-cost, low-harm preventive strategies in a pragmatic trial of effectiveness in preventing future suicidality.
The diagnosis and management of allergic reactions in patients sensitized to non‐specific lipid transfer proteins
Authors: Isabel J. Skypala, Joan Bartra, Didier G. Ebo, Margaretha Antje Faber, Montserrat Fernández‐Rivas, Francisca Gomez, Olga Luengo, Stephen J. Till, Riccardo Asero, Domingo Barber, Lorenzo Cecchi, Araceli Diaz Perales, Karin Hoffmann‐Sommergruber, Elide Anna Pastorello, Ines Swoboda, Anastasios. P. Konstantinopoulos, Ronald van Ree, Enrico Scala
Journal: Allergy (2021)

Abstract Sensitization to one or more non‐specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non‐steroidal anti‐inflammatory drugs, Cannabis sativa ) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy‐focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.
Racial, Ethnic, and Insurance-Based Disparities Upon Initiation of Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in the US
Authors: Nisha A. Malhotra, Tyler E. Greenlee, Amogh I. Iyer, Thais F. Conti, Andrew X. Chen, Rishi P. Singh
Journal: Ophthalmology (2021)