tbuckley/cabot-search huggingface dataset:
Serological tests confirm the low incidence of COVID-19 in chronic rheumatic inflammatory diseases treated with biological DMARD
Authors: Maurizio Benucci, Arianna Damiani, Gianfranco Giannasi, Francesca Li Gobbi, Luca Quartuccio, Valentina Grossi, Maria Infantino, Mariangela Manfredi
Journal: Annals of the Rheumatic Diseases (2020)

We read the interesting epidemiological study on 600 patients with rheumatic diseases hospitalised for COVID-19 infection (COVID-19 Global Rheumatology Alliance Registry) published by Gianfrancesco et al .1 Data analysis showed a slightly increased risk of hospitalisation for prednisone doses of ≥10 mg, while biological disease-modifying anti-rheumatic drug (b-DMARD)/targeted synthetic disease-modifying anti-rheumatic drug (ts-DMARD) monotherapy just prior to COVID-19 diagnosis appeared protective, in particular, the tumour necrosis factor targeting agents, as result of a subsequent subanalysis. The epidemiological impact of COVID-19 in patients with rheumatic diseases being treated with b-DMARD has been the subject of several reports by Italian groups. In the first report, only 4 cases were confirmed through rhinopharyngeal swabs out of 320 observed cases.2 In another study assessed in the emergency period in Lombardy through visit or phone contact, only 3 cases through rhinopharyngeal swabs out of 520 cases were confirmed.3 Another study of 859 patients in another rheumatology centre in Tuscany, which applied a phone contact methodology, identified only 2 patients suffering from COVID-19 pneumonia.4 As part of the Tuscany population serological screening, the Incidence COVID-19-Rheumatic Disease–Biologics study has been planned. …
Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1–4 inhibitor in patients with advanced solid tumors
Authors: R. Bahleda, F. Meric-Bernstam, L. Goyal, B. Tran, Y. He, I. Yamamiya, K.A. Benhadji, I. Matos, H.-T. Arkenau
Journal: Annals of Oncology (2020)

Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors.Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.).A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%).Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D.FOENIX-101 (ClinicalTrials.gov, NCT02052778).
Challenges of evaluating lung function as part of cancer care during the COVID-19 pandemic
Authors: Justin L. Garner, Pallav L. Shah
Journal: European Respiratory Journal (2020)

<b>The COVID-19 pandemic and the necessity for social isolation are ushering in a new era of remote clinical evaluation. Modifications of CT imaging and processing in chest medicine yield both anatomical and functional information in a safe environment.</b>https://bit.ly/2Np3Dyz
Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons
Authors: Lei Yu, Shinya Tasaki, Julie A. Schneider, Konstantinos Arfanakis, Duc M. Duong, Aliza P. Wingo, Thomas S. Wingo, Nicola Kearns, Gregory R. J. Thatcher, Nicholas T. Seyfried, Allan I. Levey, Philip L. De Jager, David A. Bennett
Journal: JAMA Psychiatry (2020)

Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.These protein signals may represent novel targets for the maintenance of cognition in old age.
Dexamethasone in the management of covid -19
Authors: Raymond M Johnson, Joseph M Vinetz
Journal: BMJ (2020)

On 16 June, investigators on the covid-19 RECOVERY trial revealed in a press release 1 that participants with severe covid-19 (2104) given 6 mg dexamethasone once daily had an 8-26% lower mortality than 4321 participants given standard care.Changes in the NHS covid-19 treatment protocol were soon announced based on these results.The results remain neither peer reviewed nor published, although a preprint is available. 2In the face of an ongoing, geographically mobile, lethal pandemic in which few highly effective-let alone affordable-treatments are available, the RECOVERY press release appropriately generated a great deal of attention, including both enthusiasm and concern.Until the RECOVERY release, the only evidence based treatment available was remdesivir-an RNA polymerase inhibitor that modestly shortens time to hospital discharge in patients with severe covid-19 3 but doesn't reduce respiratory tract viral load. 4 5RECOVERY is the first large randomised trial to test immunosuppression as a therapeutic option.It is important to note that tempering a maturing immune response to the SARS-CoV-2 virus is different from having underlying immunosuppression at the time of infection.
Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection
Authors: Marcel Doerflinger, Yexuan Deng, Paul Whitney, Ranja Salvamoser, Sven Engel, Andrew J. Kueh, Lin Tai, Annabell Bachem, Elise Gressier, Niall D. Geoghegan, Stephen Wilcox, Kelly L. Rogers, Alexandra L. Garnham, Michael A. Dengler, Stefanie M. Bader, Gregor Ebert, Jaclyn S. Pearson, Dominic De Nardo, Nancy Wang, Chenying Yang, Milton Pereira, Clare E. Bryant, Richard A. Strugnell, James E. Vince, Marc Pellegrini, Andreas Strasser, Sammy Bedoui, Marco J. Herold
Journal: Immunity (2020)

Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death pathways involved extensive cross-talk between initiators and effectors of pyroptosis and apoptosis, where initiator caspases-1 and -8 also functioned as executioners when all known effectors of cell death were absent. These findings uncover a highly coordinated and flexible cell death system with in-built fail-safe processes that protect the host from intracellular infections.
Long-term safety and tolerability of delamanid-containing regimens in multidrug-resistant and extensively drug-resistant tuberculosis patients in a specialised treatment centre in Berlin, Germany
Authors: Brit Häcker, Nicolas Schönfeld, David Krieger, Ralf Otto-Knapp, Norbert Hittel, Patricia Pflugmacher, Torsten Bauer
Journal: European Respiratory Journal (2020)

Drug-resistant tuberculosis (DR-TB) is an ongoing challenge for patients and healthcare systems. The World Health Organization (WHO) estimated 484 000 (CI: 417 000–556 000) new multidrug-resistant/rifampicin-resistant tuberculosis (MDR-/RR-TB) cases for 2018 [1]. While new and repurposed drugs show promising results in studies, notified treatment outcomes are still below expectations. Germany, as a low incidence country, had 5429 newly diagnosed TB cases (incidence rate of 6.5 per 100 000), including 118 patients with MDR-TB and eight patients with extensively drug-resistant (XDR-) TB in 2018. These data support the safety and tolerability of delamanid in the treatment of patients with MDR- and XDR-TB, even with drug exposure for longer than 6 months <https://bit.ly/3cPQQPS>
Abstract A36: Developing a novel treatment for advanced ovarian cancer by targeting the c-Met pathway
Authors: Anusha Chaparala, Wendy M. Swetzig, Anna E. Strohl, Jian-Jun Wei, Daniela Matei, Shohreh Shahabi
Journal: Clinical Cancer Research (2020)

Abstract Approximately one-third of epithelial ovarian tumors exhibit higher levels of c-Met, a receptor tyrosine kinase, activated by Hepatocyte Growth Factor (HGF). c-Met plays an important role in the growth and metastasis of tumor cells. Increased c-Met expression is associated with decreased survival and resistance to chemotherapy in various tumors. More recently, our team identified c-Met overexpression as a mechanism of resistance to neoadjuvant chemotherapy (NACT) in ovarian cancer (OC). The c-Met pathway has been explored as a therapeutic target in various solid tumors, and antibodies targeting c-Met have been proposed as novel anticancer agents. This project aims to investigate the effectiveness of a c-Met monoclonal antibody-drug conjugate (c-Met ADC) in OC models. Here we show that the anti-c-Met antibody alone effectively diminishes c-Met signaling (phosphorylation of c-Met and downstream Akt) but does not inhibit OC cell proliferation. In contrast, the c-Met ADC significantly decreases viability and induces apoptosis in c-Met-expressing OC cells. To validate c-Met expression as a predictor of resistance to NACT in OC, we analyzed c-Met expression in matched pre- and post-treatment samples collected from OC patients undergoing treatment with NACT and in a tissue microarray containing 20 ovarian tumors post-NACT. Detectable c-Met was recorded in ~50% of post-NACT specimens. We evaluated the in vitro antitumor activity of c-Met-ADC on the primary cells isolated from patients, before and after NACT, to assess tumor cell sensitivity to c-Met ADC. The results from these studies support the development of c-Met-ADC as a novel treatment for OC. Citation Format: Anusha Chaparala, Wendy M. Swetzig, Anna E. Strohl, Jian-Jun Wei, Daniela Matei, Shohreh Shahabi. Developing a novel treatment for advanced ovarian cancer by targeting the c-Met pathway [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A36.
The hepatic lipidome: From basic science to clinical translation
Authors: Marit ten Hove, Lena Pater, Gert Storm, Sabine Weiskirchen, Ralf Weiskirchen, Twan Lammers, Ruchi Bansal
Journal: Advanced Drug Delivery Reviews (2020)

The liver is the key organ involved in lipid metabolism and transport. Excessive lipid accumulation due to dysregulated lipid metabolism predisposes the liver to steatosis, cirrhosis, and hepatocellular carcinoma. Lipids are generally compartmentalized in specialized organelles called lipid droplets that enable cells to store and release lipids in a regulated manner. However, during flux-in and flux-out of droplets, lipids are converted into toxic species leading to lipid-mediated liver damage. Lipids are categorized into 'toxic' or 'healthy' lipids that are involved in liver disease pathogenesis or resolution, respectively. Lipidomic analysis have revealed unique lipid signature that correlates with the disease progression therefore being used for disease diagnosis. In this comprehensive review, we provide an overview on hepatic lipid homeostasis, lipid compartmentalization mechanisms and lipidomic profiles in different liver diseases. We further discuss promising therapeutics targeting the hepatic lipidome including pro-resolving lipids, liposomes, and small-molecule inhibitors for the treatment of liver diseases.
Varicose veins in primary care
Authors: Eleanor Atkins, Nadeem A Mughal, Fiona Place, Patrick A Coughlin
Journal: BMJ (2020)

### What you need to know

A 62 year old woman presents to her general practitioner with bilateral lower leg swelling and aching. She has extensive varicose veins on both legs which developed during her last pregnancy, 25 years ago. She has experienced increasing discomfort in both legs over the past five years and lower leg swelling which worsens during the day. She has started to develop some eczematous skin changes around the ankle of the right leg. 

Annually, 1-2% of people with skin changes related to varicose veins develop lower limb ulceration,1 which affects their quality of life and creates socioeconomic burdens on health services.1 Each year up to 7% of people with varicose veins develop lower leg skin changes (such as haemosiderin deposition and/or lipodermatosclerosis),1 which are a sign that they are at increased risk of slow wound healing and ulceration. Ulceration and skin changes are both signs of chronic venous insufficiency and require treatment. Timely specialist referral can reduce the impact on quality of life and reduce costs.2

This article offers guidance to general practitioners and non-specialists on the assessment of patients presenting with varicose veins, how to recognise chronic venous insufficiency, when to refer to secondary care, and appropriate management strategies that can be initiated in primary care. We also provide a summary of management options that might be considered in secondary care.

The advice offered in this paper is based on our clinical experience as well as the limited evidence that is available on non-specialist assessment and management of varicose …
Assessment of Community Interventions for Bystander Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
Authors: Yang Yu, Qingtao Meng, Sonali Munot, Tu N. Nguyen, Julie Redfern, Clara K. Chow
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Outcomes from out-of-hospital cardiac arrests (OHCAs) remain poor. Outcomes associated with community interventions that address bystander cardiopulmonary resuscitation (CPR) remain unclear and need further study. <h3>Objective</h3> To examine community interventions and their association with bystander CPR and survival after OHCA. <h3>Data Sources</h3> Literature search of the MEDLINE, Embase, and the Cochrane Library databases from database inception to December 31, 2018, was conducted. Key search terms included<i>cardiopulmonary resuscitation</i>,<i>layperson</i>,<i>basic life support</i>,<i>education</i>,<i>cardiac arrest</i>, and<i>survival</i>. <h3>Study Selection</h3> Community intervention studies that reported on comparisons with control and differences in survival following OHCA were included. Studies that focused only on in-hospital interventions, patients with in-hospital cardiac arrest, only dispatcher-assisted CPR, or provision of automated external defibrillators were excluded. <h3>Data Extraction and Synthesis</h3> Pooled odds ratios (ORs) and 95% CIs were estimated using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. <h3>Main Outcomes and Measures</h3> Thirty-day survival or survival to hospital discharge and bystander CPR rate. <h3>Results</h3> A total of 4480 articles were identified; of these, 15 studies were included for analysis. There were broadly 2 types of interventions: community intervention alone (5 studies) and community intervention combined with changes in health services (10 studies). Four studies involved notification systems that alerted trained lay bystanders to the location of the OHCA in addition to CPR skills training. Meta-analysis of 9 studies including 21 266 patients with OHCA found that community interventions were associated with increased survival to discharge or 30-day survival (OR, 1.34; 95% CI, 1.14-1.57;<i>I</i><sup>2</sup> = 33%) and greater bystander CPR rate (OR, 1.28; 95% CI, 1.06-1.54;<i>I</i><sup>2</sup> = 82%). Compared with community intervention alone, community plus health service intervention was associated with a greater bystander CPR rate compared with community alone (community plus intervention: OR, 1.74; 95% CI, 1.26-2.40 vs community alone: OR, 1.06; 95% CI, 0.85-1.31) (<i>P</i> = .01). Survival rate, however, was not significantly different between intervention types: community plus health service intervention OR, 1.71; 95% CI, 1.09-2.68 vs community only OR, 1.26; 95% CI, 1.05-1.50 (<i>P</i> = .21). <h3>Conclusions and Relevance</h3> In this study, while the evidence base is limited, community-based interventions with a focus on improving bystander CPR appeared to be associated with improved survival following OHCA. Further evaluations in diverse settings are needed to enable widespread implementation of such interventions.
Covid-19: unjustified risk to people held in immigration removal centres
Authors: Mary Kamara, Rachel Bingham
Journal: BMJ (2020)

We agree with McKee and colleagues that any delay in finding solutions to the challenges of covid-19 must be avoided.1 As they say, there is a disproportionate burden on ethnic minority populations,2 including those held in immigration removal centres for administrative reasons before potential removal to their country of origin.

Experts warned that these institutionalised settings could function as “epidemiological pumps,” and recommended urgent measures to prevent the spread of infection.3 …
Postpancreatitis Diabetes Confers Higher Risk for Pancreatic Cancer Than Type 2 Diabetes: Results From a Nationwide Cancer Registry
Authors: Jaelim Cho, Robert Scragg, Maxim S. Petrov
Journal: Diabetes Care (2020)

OBJECTIVE Pancreatitis and diabetes are established risk factors for pancreatic cancer. However, to date, studies have investigated only the risk associated with either of them alone. The aim of this study was to investigate the effect of pancreatitis and diabetes combined, as well as their temporal relationship, on the risk of pancreatic cancer. RESEARCH DESIGN AND METHODS Nationwide cancer registry was linked to hospital discharge and mortality data from 1998 to 2015 in New Zealand. Incidence of primary pancreatic cancer in the four study groups (type 2 diabetes [T2D] alone, pancreatitis alone, T2D followed by pancreatitis, and postpancreatitis diabetes mellitus [PPDM]) was identified. Multivariable Cox regression analyses were conducted, with T2D as the reference group. A head-to-head comparison between the T2D followed by pancreatitis and PPDM groups was also performed. RESULTS Among 139,843 individuals (735,541 person-years), 913 (0.7%) were diagnosed with pancreatic cancer. The proportion of pancreatic cancer was 3.1%, 2.3%, 2.0%, and 0.6% in individuals with PPDM, T2D followed by pancreatitis, pancreatitis alone, and T2D alone, respectively. PPDM (hazard ratio [HR] 6.94; 95% CI 4.09–11.77) and T2D followed by pancreatitis (HR 5.35; 95% CI 3.52–8.14) were associated with significantly higher risks of pancreatic cancer compared with T2D alone. In the head-to-head comparison, PPDM was associated with a higher risk of pancreatic cancer compared with T2D followed by pancreatitis (HR 2.35; 95% CI 1.12–4.93). CONCLUSIONS Pancreatitis significantly increases the risk of pancreatic cancer in individuals with diabetes. In particular, PPDM poses the highest risk for pancreatic cancer.
Dynamics in protein translation sustaining T cell preparedness
Authors: Tobias Wolf, Wenjie Jin, Giada Zoppi, Ian A. Vogel, Murodzhon Akhmedov, Christopher K. E. Bleck, Tim Beltraminelli, Jan C. Rieckmann, Neftali J. Ramirez, Marco Benevento, Samuele Notarbartolo, Dirk Bumann, Felix Meissner, Bodo Grimbacher, Matthias Mann, Antonio Lanzavecchia, Federica Sallusto, Ivo Kwee, Roger Geiger
Journal: Nature Immunology (2020)
Reply to “Comment on: ‘Children with chronic urticaria can be effectively controlled with updosing second-generation antihistamines’”
Authors: Sofianne Gabrielli, Michelle Le, Elena Netchiporouk, Barbara Miedzybrodzki, Sharon Baum, Shoshana Greenberger, Petra Staubach-Renz, Moshe Ben-Shoshan
Journal: Journal of the American Academy of Dermatology (2020)
Risk of COVID-19 in dermatologic patients receiving long-term immunomodulatory therapy
Authors: Zachary E. Holcomb, Monica Rosales Santillan, Peyton C. Morss-Walton, Prerna Salian, Min Ji Her, Nicole M. Giannotti, Alexa B. Kimball, Martina L. Porter
Journal: Journal of the American Academy of Dermatology (2020)