tbuckley/cabot-search huggingface dataset:
Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review
Authors: Howard Lim, Ravi Ramjeesingh, Dave Liu, Vincent C Tam, Jennifer J Knox, Paul B Card, Brandon M Meyers
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background: Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. Methods: Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms “hepatocellular cancer” AND “advanced” AND “targeted therapy” AND “phase III” OR respective aliases (PRISMA). Results: Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. Conclusions: Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.
Insulin dose optimization using an automated artificial intelligence-based decision support system in youths with type 1 diabetes
Authors: Revital Nimri, Tadej Battelino, Lori M. Laffel, Robert H. Slover, Desmond Schatz, Stuart A. Weinzimer, Klemen Dovc, Thomas Danne, Moshe Phillip, Moshe Phillip, Revital Nimri, Shlomit Shalitin, Rachel Bello, Michal Nevo-Shenker, Naama Fisch-Shvalb, Galit Shiovitch-Mantzuri, Orit Choresh, Irit Drutz, Yehiel Nava, Alona Hemo, Orna Hermon, Rachel Nave, Tadej Battelino, Klemen Dovc, Natasa Bratina, Darja Smigoe-Schweiger, Brigita Mali, Ana Gianini, Urska Sever, Barbara Murn Berkopec, Lori M. Laffel, Michelle Katz, Elvira Isganaitis, Sanjeev Mehta, Heidi Quinn, Nisha Naik, Zijing Guo, Lisa Volkening, Robert H. Slover, Gregory Forlenza, R. Paul Wadwa, G. Todd Alonso, Laurel Messer, Lindsey Towers, Katie Thivener, Cari Berget, Samantha Lange, Emily Jost, Maria Rossick-Solis, Desmond Schatz, Michael Haller, Paul Hiers, Laura Jacobsen, Madison Smith, Anastasia O’Neill, Jennifer Hosford, Alexis Perry, Stuart A. Weinzimer, Eda Cengiz, Jennifer Sherr, Kathryn Gibbons, Lori Carria, Melinda Zgorski, Thomas Danne, Torben Biester, Olga Kordonouri, Thekla von dem Berge, Sarah Biester, Kerstin Remus
Journal: Nature Medicine (2020)
Considerations for Optimal Device Selection in Transcatheter Aortic Valve Replacement
Authors: Bimmer E. Claessen, Gilbert H. L. Tang, Annapoorna S. Kini, Samin K. Sharma
Journal: JAMA Cardiology (2020)

<h3>Importance</h3> Aortic valve stenosis (AS) is the most common manifestation of acquired valvular heart disease in developed countries. Several large-scale randomized clinical trials investigating the entire spectrum of patients with severe symptomatic AS from low to prohibitive risk have established transcatheter aortic valve replacement (TAVR) as a safe and effective alternative to surgical aortic valve replacement. <h3>Observations</h3> There are currently only 3 types of TAVR devices commercially available in the US, but several other valve types are undergoing clinical trials in the US. Because of fundamental differences in engineering features, each TAVR device type has specific strengths and limitations. This review aims to provide an overview of design features and clinical outcomes of various TAVR devices that are either commercially available or undergoing clinical investigation. <h3>Conclusions and Relevance</h3> Given the lack of large-scale head-to-head comparisons of various TAVR devices and the rapid development of new device iterations, there is insufficient evidence to claim superiority of one device type over another. Nonetheless, as each TAVR device has unique design characteristics, certain patient-related and anatomy-related factors may slightly favor one or several particular designs.
Correction: Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-HF registry
Authors: Jasper Tromp, Wan Ting Tay, Wouter Ouwerkerk, Tiew-Hwa Katherine Teng, Jonathan Yap, Michael R. MacDonald, Kirsten Leineweber, John J. V. McMurray, Michael R. Zile, Inder S. Anand, A. Mark Richards, Carolyn S. P. Lam
Journal: PLoS Medicine (2018)

[This corrects the article DOI: 10.1371/journal.pmed.1002541.].
Neil Douglas: sleep researcher and co-founder of the Faculty of Medical Leadership and Management
Authors: Joanna Lyall
Journal: BMJ (2020)

In an early job interview Neil Douglas was asked by a professor what his career plans were “when all this sleep business is over.”

Douglas, who has died at the age of 71, then made development of his specialty and research into treatments for sleep disorders the main planks of his working life. He founded Edinburgh’s Sleep Centre, one of the first of its kind, in 1983 and the British Sleep Society six years later. “Many thought we were from the lunatic fringe trying to establish sleep as a branch of medicine in the UK,” he said. “I felt inviting some international speakers to enthuse the struggling UK workers would help.”

In 1994 he published a landmark randomised controlled study of the effectiveness of continuous positive airway pressure (CPAP) for patients with sleep apnoea,1 and further research led to NHS funding for sleep services. “Which was precisely my intention,” said Douglas.

In 1995 Edinburgh University awarded …
Therapeutic responses to <i>Roseomonas mucosa</i> in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair
Authors: Ian A. Myles, Carlo R. Castillo, Kent D. Barbian, Kishore Kanakabandi, Kimmo Virtaneva, Emily Fitzmeyer, Monica Paneru, Francisco Otaizo-Carrasquero, Timothy G. Myers, Tovah E. Markowitz, Ian N. Moore, Xue Liu, Marc Ferrer, Yosuke Sakamachi, Stavros Garantziotis, Muthulekha Swamydas, Michail S. Lionakis, Erik D. Anderson, Noah J. Earland, Sundar Ganesan, Ashleigh A. Sun, Jenna R.E. Bergerson, Robert A. Silverman, Maureen Petersen, Craig A. Martens, Sandip K. Datta
Journal: Science Translational Medicine (2020)

Roseomonas mucosa treatment in children with atopic dermatitis is associated with clinical improvements and potentially lipid-mediated TNF signaling.
Patterns of cutaneous immune‐related adverse events in adults and children with advanced sarcoma: a retrospective cohort study
Authors: L.L. Thompson, M.S. Chang, L. McCormack, N. Polyakov, J. Yoon, H. Song, J.T. Huang, S.T. Chen
Journal: British Journal of Dermatology (2020)

Immune checkpoint inhibitors (ICIs) have improved survival for multiple malignancies in adults and children.1,2 However, their benefits are tempered by a range of serious immune-related adverse events (irAEs). 1,2 Among these, cutaneous irAEs (cirAEs) represent one of the most common subtypes, impacting approximately one-third of adult patients receiving ICIs.1,3 The patterns and significance of cirAEs in children remain unclear, largely because these reactions have not been evaluated in detail.
The UCSC SARS-CoV-2 Genome Browser
Authors: Jason D. Fernandes, Angie S. Hinrichs, Hiram Clawson, Jairo Navarro Gonzalez, Brian T. Lee, Luis R. Nassar, Brian J. Raney, Kate R. Rosenbloom, Santrupti Nerli, Arjun A. Rao, Daniel Schmelter, Alastair Fyfe, Nathan Maulding, Ann S. Zweig, Todd M. Lowe, Manuel Ares, Russ Corbet-Detig, W. James Kent, David Haussler, Maximilian Haeussler
Journal: Nature Genetics (2020)
Novel ultrathin double-balloon endoscopy for the diagnosis of small-bowel diseases: a multicenter nonrandomized study
Authors: Masanao Nakamura, Tomonori Yano, Motohiro Esaki, Shiro Oka, Keigo Mitsui, Fumihito Hirai, Keisuke Kawasaki, Mitsuhiro Fujishiro, Takehiro Torisu, Shinji Tanaka, Katsuhiko Iwakiri, Masahiro Kishi, Takayuki Matsumoto, Hironori Yamamoto
Journal: Endoscopy (2020)

Background This study aimed to compare the markers of potential pancreatic injury during antegrade double-balloon endoscopy (DBE) using the newly developed ultrathin EN-580XP system and the conventional EN-580T system. Methods Patients who were scheduled for antegrade DBE during daily clinical practice were enrolled. Clinical background, adverse events, and laboratory data of patients were compared between those who underwent endoscopy using the EN-580XP system and those in whom the EN-580T system was used. The primary end points were pancreatic hyperamylasemia and hyperlipasemia after DBE. Results A total of 295 cases were registered. Pancreatic hyperamylasemia occurred in 2 of 92 patients (2.2 %) in the EN-580XP group and in 28 of 147 patients (19.1 %) in the EN-580 T diagnosis group (P &lt; 0.001). Hyperlipasemia was significantly different between the two groups (1.1 % [EN-580XP] vs. 13.6 % [EN-580 T diagnosis]; P &lt; 0.001). Acute pancreatitis occurred in four patients (7.1 %) in the EN-580 T therapy group. Multiple logistic regression analyses revealed that the endoscope type EN-580 T was significantly associated with pancreatic hyperamylasemia (adjusted odds ratio [OR] 8.63, 95 % confidence interval [CI] 1.97 – 37.70; P &lt; 0.01) and hyperlipasemia (adjusted OR 13.10, 95 %CI 1.70 – 100.70; P = 0.01). Conclusions The EN-580XP system seemed less harmful to the pancreas during antegrade DBE.
Use of nasal high flow oxygen during acute respiratory failure
Authors: Jean-Damien Ricard, Oriol Roca, Virginie Lemiale, Amanda Corley, Jens Braunlich, Peter Jones, Byung Ju Kang, François Lellouche, Stefano Nava, Nuttapol Rittayamai, Giulia Spoletini, Samir Jaber, Gonzalo Hernandez
Journal: Intensive Care Medicine (2020)
How Does Behavioural Activation Work? A Systematic Review of the Evidence on Potential Mediators
Authors: Noortje P. Janssen, Gert-Jan Hendriks, Céline T. Baranelli, Peter Lucassen, Richard Oude Voshaar, Jan Spijker, Marcus J.H. Huibers
Journal: Psychotherapy and Psychosomatics (2020)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Behavioural activation is an effective treatment for depression, but little is known about its working mechanisms. Theoretically, its effect is thought to rely on an interplay between activation and environmental reward. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; The present systematic review examines the mediators of behavioural activation for depression. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A systematic literature search without time restrictions in Medline, EMBASE, PsycINFO, The Cochrane Library, and CINAHL resulted in 14 relevant controlled and uncontrolled prospective treatment studies that also performed formal mediation analyses to investigate their working mechanisms. After categorising the mediators investigated, we systematically compared the studies’ methodological quality and performed a narrative synthesis of the findings. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Most studies focused on activation or environmental reward, with 21 different mediators being investigated using questionnaires that focused on psychological processes or beliefs. The evidence for both activation and environmental reward as mediators was weak. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Non-significant results, poor methodological quality of some of the studies, and differences in questionnaires employed precluded any firm conclusions as to the significance of any of the mediators. Future research should exploit knowledge from fundamental research, such as reward motivation from neurobiology. Furthermore, the use of experience sampling methods and idiographic analyses in bigger samples is recommended to investigate potential causal pathways in individual patients.
SAT0723-HPR INVESTIGATION OF FUNCTIONAL CAPACITY AND AFFECTING FACTORS IN SYSTEMIC SCLEROSIS PATIENTS
Authors: Hazal Yakut, Sevgi Özalevli, Aylin Özgen Alpaydin, Gerçek Can
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic Sclerosis (SSc) is a rare, systemic connective tissue disease characterized by widespread microvascular damage and by increased production and deposition of extracellular matrix components both in the skin and internal organs (1). <h3>Objectives</h3> The aim of this study was to investigate the functional capacity and affecting factors in SSc patients. <h3>Methods</h3> Twenty-two SSc patients were included in the study. Functional capacities of patients were measured by 6 Minute Walking Test (6MWT). Lung volumes (FVC, FEV1, FEV1/FVC, PEF, VC) were performed with Pulmonary function tests-PFT. Respiratory muscle strength was evaluated with a muscle inspiratory pressure(MIP)-muscle expiratory pressure(MEP) modulated spirometer known as respiratory muscle strength meter. Peripheral muscle strengths (deltoid, biceps, quadriceps and iliopsoas muscles) were also evaluated with manual muscle strength meter. <h3>Results</h3> The mean age of the patients was 52.00±11.23 years and duration of diagnosis was 7.63±4.86 years. The patients' mean 6DWT distance was 430.40±50.25 meters, FEV1% were 78.52±22. 23 L, FVC% were 80.95±23.02 L, FEV1/FVC% were 102.56±9.58 L, VC% values were 72.95±22.75 L, MIP% were 54.27±34.85 L, and MEP% values were 56.59±3.56. The mean deltoid muscle strength of the patients was 5.88±1.26 kg, biceps were 6.48±1.68 kg, quadriceps were 6.06±1.55 kg, iliopsoas were 5.93±1.74 kg. It was found that there was a significant correlation between 6MWT distance and VC (p =0.009, r = 0.529), FEV1 (p =0.001, r = 0.659), FVC (p =0.005, r = 0.568), MIP (p =0.014, r = 0.506) and MEP (p =0.036, r = 0.449). There was significant correlation between the 6MWT distance and Deltoideus (p =0.024, r = 0.470), Biceps (p =0.001, r = 0.646), Quadriceps (p&lt;0.001, r = 0.679) and İliopsoas (p=0.004, r = 0.576) muscles strengths. <h3>Conclusion</h3> The decrease in the functional capacity of the patients is accompanied by a decrease in pulmonary function, loss of respiratory and peripheral muscle strength in parallel. 6-min walk test showed negative effects in the pulmonary and musculoskeletal system or in the patients' clinic on SSc patients. To evaluate and improve functional capacity while performing medical and rehabilitation follow-up, respiratory functions, respiratory and peripheral muscle strengths should be evaluated and improved. <h3>Reference</h3> [1] Hinchcliff, M., &amp; Varga, J. (2008). Systemic sclerosis/scleroderma: A treatable multisystem disease. American Family Physician, 78(8), 961–968. <h3>Disclosure of Interests</h3> None declared
BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity
Authors: Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Anne H. Shen, Danilo Pellin, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Jasmine Bonanno, Aylin C. Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Theresa Engels, Robert E. Donahue, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Shaina N. Porter, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell J. Weiss, Shondra M. Pruett-Miller, Scot A. Wolfe, Daniel E. Bauer, John F. Tisdale
Journal: Journal of Clinical Investigation (2020)

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from patients with sickle cell disease (SCD) induces fetal hemoglobin (HbF) without detectable toxicity, as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer–edited HSPCs in 4 nonhuman primates. We used a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer– or control locus–targeted (AAVS1-targeted) cells. Biallelic BCL11A enhancer editing resulted in robust γ-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Nonhomologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we found that edited HSCs can persist for at least 101 weeks after transplant and biallelic-edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach.
Knowledge before belief
Authors: Jonathan Phillips, Wesley Buckwalter, Fiery Cushman, Ori Friedman, Alia Martin, John Turri, Laurie Santos, Joshua Knobe
Journal: Behavioral and Brain Sciences (2020)

Research on the capacity to understand others' minds has tended to focus on representations of beliefs, which are widely taken to be among the most central and basic theory of mind representations. Representations of knowledge, by contrast, have received comparatively little attention and have often been understood as depending on prior representations of belief. After all, how could one represent someone as knowing something if one does not even represent them as believing it? Drawing on a wide range of methods across cognitive science, we ask whether belief or knowledge is the more basic kind of representation. The evidence indicates that nonhuman primates attribute knowledge but not belief, that knowledge representations arise earlier in human development than belief representations, that the capacity to represent knowledge may remain intact in patient populations even when belief representation is disrupted, that knowledge (but not belief) attributions are likely automatic, and that explicit knowledge attributions are made more quickly than equivalent belief attributions. Critically, the theory of mind representations uncovered by these various methods exhibits a set of signature features clearly indicative of knowledge: they are not modality-specific, they are factive, they are not just true belief, and they allow for representations of egocentric ignorance. We argue that these signature features elucidate the primary function of knowledge representation: facilitating learning from others about the external world. This suggests a new way of understanding theory of mind - one that is focused on understanding others' minds in relation to the actual world, rather than independent from it.
CD4 <sup>+</sup> T-Cell Endogenous Cystathionine γ Lyase–Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation
Authors: Changting Cui, Jinghui Fan, Qiang Zeng, Junyan Cai, Yongzeng Chen, Zhenzhen Chen, Wenjie Wang, Shuang yue Li, Qinghua Cui, Jichun Yang, Chaoshu Tang, Guoheng Xu, Jun Cai, Bin Geng
Journal: Circulation (2020)

Hydrogen sulfide (H2S) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4+ T cells. However, the role of CD4+ T-cell endogenous CSE/H2S in the development of hypertension is unclear.Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then H2S production and expression of its generation enzymes, cystathionine β synthase and CSE, were measured to determine the major H2S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4cre mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H2S system.In lymphocytes, H2S from CSE, but not cystathionine β synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between H2S production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mm Hg) under the physiological condition and exacerbated angiotensin II-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4+ and CD8+ T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4+ T cell transfer into CD4 null mice, also showed the similar phenotypes' confirming the role of endogenous CSE/H2S action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout-induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/H2S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation.The constitutive sulfhydration of liver kinase B1 by CSE-derived H2S activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.
Identifying key components and therapeutic targets of the immune system in hidradenitis suppurativa with an emphasis on neutrophils
Authors: S. Narla, M. Azzam, S. Townsend, G. Vellaichamy, A.V. Marzano, A. Alavi, M.A. Lowes, I.H. Hamzavi
Journal: British Journal of Dermatology (2020)

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent and debilitating skin disease of the hair follicle unit that typically develops after puberty. The disorder is characterized by comedones, painful inflammatory nodules, abscesses, dermal tunnels and scarring, with a predilection for intertriginous areas of the body (axillae, inguinal and anogenital regions). Recruitment of neutrophils to HS lesion sites may play an essential role in the development of the painful inflammatory nodules and abscesses that characterize the disease. This is a review of the major mediators involved in the recruitment of neutrophils to sites of active inflammation, including bacterial components (endotoxins, exotoxins, capsule fragments, etc.), the complement pathway anaphylatoxins C3a and C5a, tumour necrosis factor-alpha, interleukin (IL)-17, IL-8 (CXCL8), IL-36, IL-1, lipocalin-2, leukotriene B4, platelet-activating factor, kallikreins, matrix metalloproteinases, and myeloperoxidase inhibitors. Pharmacological manipulation of the various pathways involved in the process of neutrophil recruitment and activation could allow for successful control and stabilization of HS lesions and the remission of active, severe flares.