tbuckley/cabot-search huggingface dataset:
Effect of food on exposure to napabucasin: Data from two phase I studies.
Authors: Xiaoshu Dai, Naoto Noda, Yuran Xie, Bo Xu, Matthew Hitron, Michael Karol
Journal: Journal of Clinical Oncology (2021)

477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, C max increased by 15% and AUC last by ~60% (Table), while t max decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, C max increased by 21% and AUC last by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (C max ; AUC last ; AUC inf ) and decreased t max vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (C max ; AUC last ) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]
Mast cell‐derived serotonin enhances methacholine‐induced airway hyperresponsiveness in house dust mite‐induced experimental asthma
Authors: Erika Mendez‐Enriquez, Perla Abigail Alvarado‐Vazquez, Willem Abma, Oscar E. Simonson, Sergey Rodin, Thorsten B. Feyerabend, Hans‐Reimer Rodewald, Andrei Malinovschi, Christer Janson, Mikael Adner, Jenny Hallgren
Journal: Allergy (2021)

Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown.Cpa3Cre/+ mice, which lack mast cells, were used to assess the role of mast cells in house dust mite (HDM)-induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function and in lung mast cells in vitro. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation, and HDM-induced bronchoconstriction were evaluated.Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc-receptors, or antagonizing serotonin (5-HT)2A receptors abolished HDM-induced trachea contractions. HDM-sensitized mice lacking mast cells had diminished lung-associated 5-HT levels, reduced AHR and methacholine-induced airway contraction, while blocking 5-HT2A receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5-HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5-HT intracellularly, and methacholine induces release of 5-HT from lung-derived mouse mast cells and Ca2+ flux in human LAD-2 mast cells.Methacholine activates mast cells to release 5-HT, which by acting on 5-HT2A receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.
Neutrophil/lymphocyte ratio as a predictor of lymph node metastasis in extramammary Paget disease: A retrospective study
Authors: Aoi Ebata, Tomoki Taki, Shoichiro Mori, Yoshie Murakami, Toru Urata, Mao Okumura, Honami Akanabe, Satoko Imai, Kenji Yokota, Masashi Akiyama
Journal: Journal of the American Academy of Dermatology (2021)
Gene-Targeting Therapeutics for Neurological Disease: Lessons Learned from Spinal Muscular Atrophy
Authors: Bhavya Ravi, Michelle Harran Chan-Cortés, Charlotte J. Sumner
Journal: Annual Review of Medicine (2021)

The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.
AB0673 SHINING LIGHT ON AXIAL SPONDYLOARTHRITIS: DISEASE ACTIVITY AND VITAMIN D. WHAT’S THE LINK?
Authors: G. A. Brown, K. M. Torsney, E. Nikiphorou
Journal: Annals of the Rheumatic Diseases (2020)

Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly involving the axial skeleton and sacroiliac joints. Although the exact aetiology remains largely unknown, there is thought to be an immune-driven element. Vitamin D deficiency has been associated with a number of autoimmune diseases and is thought to play an important role in modulating the immune system. Low vitamin D levels may contribute to the development and progression of axSpA 1 . Objectives: To study the possible associations between low vitamin D and disease activity in axSpA. Methods: A systematic literature search using Medline, Embase and Cochrane was performed using MESH search terms “ankylosing spondylitis”, “axial spondyloarthropathy” and “vitamin D”. Articles examining disease activity measured by BASDAI, ASDAS-CRP, ESR and CRP identified through title/abstract screening, were included in the study, with relevant information extracted. Results: Out of 495 articles identified from the initial search, 19 observational studies which were mostly (89%) cross-sectional studies were identified. There was considerable heterogeneity between studies, including in the definition of vitamin D deficiency, latitude where study took place and seasonal variation. Vitamin D levels were often lower in patients with axSpA compared to controls. Seventeen studies found no association with vitamin D deficiency and disease activity. The exceptions included one study which measured serum vitamin D receptor levels as opposed to serum 25 (OH) D or 1,25 (OH)2 D concentrations, and another study whose recruitment occurred over four years and therefore seasonal variation may conflict results. Patients taking NSAIDs or anti-TNF had no difference in vitamin D levels. Conclusion: Vitamin D deficiency is more prevalent in axSpA but does not seem to associate with increased disease activity. Longitudinal studies are required to better define these links. References: [1]Sizheng Z, et al. Systematic review of association between vitamin D levels and susceptibility and disease activity of ankylosing spondylitis. Rheumatology 2014; 53:1595-1603. Disclosure of Interests: None declared
A phase I/II trial to evaluate cabozantinib in patients with advanced hepatocellular carcinoma with Child-Pugh class B cirrhosis after first-line therapy.
Authors: Thomas Enzler, Neehar Parikh, Chih-Yi Liao, Aparna Kalyan, David Hsieh, Kent A. Griffith, Vaibhav Sahai
Journal: Journal of Clinical Oncology (2021)

TPS357 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer related death worldwide. HCC typically develops in patients with cirrhosis and has a 5-year survival estimate of 20%. Only patients with early stage disease may be eligible for a curative approach using local treatment and/or transplant. The majority of patient present with advanced HCC and will require systemic treatment for disease control. Several systemic therapies are FDA-approved for the treatment of HCC; however, they are only approved for patients with Child-Pugh class A cirrhosis. There are limited data and no approved second-line therapy for HCC with more advanced cirrhosis, including Child-Pugh class B, which represents a significant proportion of patients. The aim of this trial is to determine the safety and efficacy of cabozantinib, a multi-kinase inhibitor, in patients with HCC with Child-Pugh class B cirrhosis. Methods: This investigator-initiated, phase I/II study is enrolling 32 patients with advanced HCC, Child-Pugh B7 or B8, who have previously received first-line systemic treatment. Patients receive cabozantinib at one of 3 dose levels (20 mg, 40 mg, and 60 mg) with a starting dose level of 40 mg to evaluate the safety profile and obtain the recommended phase 2 dose (RP2D). The primary endpoint is assessment of dose-limiting toxicity with a null hypothesis greater than 35%. Secondary endpoints include ORR per RECIST v1.1, PFS, OS, and PK profile. Exploratory endpoints include whole exome/RNAseq analysis (including MET, VEGF, AXL, and immune signature), spatial profiling of immune markers by multiplex immunofluorescence, and specimen banking (tissue, blood and imaging). The trial design is based on the Time-To-Event modification of the Continual Reassessment Method (TiTE-CRM), which allows for continued monitoring of toxicity as a function of a dose-over-time, and is flexible with regard to the number of patients treated at a certain dose. The trial is open at University of Michigan as lead and coordinating site, and due to open at 3 additional high-volume centers. Clinical trial information: 04497038.
Phase II study of pembrolizumab after chemoradiotherapy (CRT) as adjuvant therapy for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients at high risk of recurrence following preoperative CRT plus surgery.
Authors: Chih-Hung Hsu, Jhe-Cyuan Guo, Ta-Chen Huang, Hung-Yang Kuo, Chia-Chi Lin, Feng-Ming Hsu, Jason C. Cheng, Pei-Ming Huang, Jang-Ming Lee
Journal: Journal of Clinical Oncology (2021)

TPS259 Background: LA-ESCC is a potentially curable disease, for which preoperative CRT followed by esophagectomy is a standard-of-care. Previous studies have identified that close/involved margin and lymph node metastasis with extranodal invasion (ENI) in post-CRT surgical specimens are associated with increased risk of recurrence. In CheckMate-577 trial, adjuvant nivolumab significantly improved disease-free survival (DFS) in patients with esophageal cancer treated with preoperative CRT and surgery; in another trial (the “PACIFIC” trial), adjuvant durvalumab has significantly improved overall survival (OS) in stage III non-small cell lung cancer treated with definitive CRT. We hypothesize that adding pembrolizumab to CRT as an adjuvant therapy would improve the outcomes of LA-ESCC patients who are treated with preoperative CRT plus esophagectomy and with high-risk of recurrence. Methods: This single institution single-arm phase II study include patients with histologically confirmed LA-ESCC (AJCC 7th staging system:cT3-4aN0M0 or T1-4aN1-3M0) harboring at least one risk factor (closed/involved margin, ENI, or ypN2-3) in post-CRT surgical specimens. Patients with adenocarcinoma of esophagus or gastroesophageal junction or synchronously diagnosed with a squamous cell carcinoma of aero-digestive way other than ESCC are excluded. Patients enrolled will receive adjuvant weekly cisplatin–CRT (cisplatin, 30mg/m 2 for 2 cycles every week; radiotherapy, 180-200 cGy/fraction for 10-13 times) followed by pembrolizumab (200 mg, every 3 weeks, for 18 cycles). The primary endpoint of this study is 1-year relapse-free survival (RFS) rate; and the key secondary endpoints include RFS, 3-year RFS rate, OS, 3-yr OS rate, toxicity and safety. The study, registered with clinical trial ID of NCT03322267, started patient enrollment in Aug 2018. As of Aug of 2020, 11 of 46 planned patients have been enrolled. Clinical trial information: NCT03322267.
Liver function test abnormalities at hospital admission are associated with severe course of SARS-CoV-2 infection: a prospective cohort study
Authors: Sabine Weber, Johannes C Hellmuth, Clemens Scherer, Maximilian Muenchhoff, Julia Mayerle, Alexander L Gerbes
Journal: Gut (2021)

Objective Liver injury has frequently been reported in COVID-19 patients. The clinical relevance of liver injury related to SARS-CoV-2 infection remains unclear with a need for prospective studies on the impact of liver function test (LFT) abnormalities at baseline. Design Data of 217 patients without pre-existing liver disease prospectively included in the COVID-19 registry of the LMU university hospital were analysed in order to assess the association of abnormal LFT at admission and course of the disease. Severe course was defined as admission to the intensive care unit (ICU) or as COVID-19-related death. Results Abnormal LFT at baseline was present in 58% of patients, with a predominant elevation of aspartate aminotransferase (AST) (42%), gamma-glutamyltransferase (GGT) (37%) and alanine aminotransferase (ALT) (27%), hypoalbuminaemia was observed in 33%. Elevation of ALT and GGT, as well as hypoalbuminaemia, was associated with higher proportions of patients requiring ICU treatment and mechanical ventilation. After adjusting for age, gender and comorbidities, hypoalbuminaemia combined with abnormal AST or GGT at hospital admission was a highly significant independent risk factor for ICU admission (OR 46.22 and 38.8, respectively) and for a composite endpoint of ICU admission and/or COVID-19-related death (OR 42.0 and 26.9, respectively). Conclusion Abnormal LFTs at hospital admission, in particular GGT and albumin, are associated with a severe course of SARS-CoV-2 infection.
Kirsty Annabel Gillgrass
Authors: Sarah Costen, George Scott Davison
Journal: BMJ (2021)

From a young age, Kirsty Annabel Gillgrass (nee Smith) excelled in everything she did, in many realms. She met her future husband, Jon, while training in Sheffield. After house jobs and VTS training in Barnsley, she qualified in 2009 and returned to Sheffield. Her dynamism and energy were pivotal in …
OP0135 Healthcare resource use among users of nonsteroidal anti-inflammatory drugs in italy
Authors: AP Caputi, A Russo, SX Kong, P Mavros, E Ricci
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Severe upper gastrointestinal (GI) complications such as perforation, ulcer or bleeding are associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs). Most adverse drug reactions (ADRs) related to NSAIDs are non-life threatening, yet they represent a considerable amount of healthcare resource use. <h3>Objectives</h3> Evaluate the use of health care resources associated with GI complications among NSAID users in Italy. <h3>Methods</h3> From December 1998 to June 1999, 103 general practitioners in the Sicily region of Italy were asked to record data in 10 consecutive days on all patients who visited their offices. Physicians were instructed to fill out data collection forms regarding the type and indication of NSAIDs used and the use of medical resources (eg physician visits, specialist consultations, diagnostic tests, and hospitalizations) related to NSAIDs in general practice for the 6-month period prior to the visit. Physicians were also asked to indicate whether any patient visits during the past six months were related to NSAID ADRs. <h3>Results</h3> A total of 913 NSAID users were identified among 20,668 patients who visited the physicians’ offices. The mean age of the patients was 61 years and 61% were females. About 47% filled more than one NSAID prescription during the 6-month period prior to the visit. Of all NSAID users, 50.3% used at least one GI protective agent (including proton pump inhibitors, H2-antagonists, misoprostol and prescription or OTC antacids). There were on average five physician visits per patient. Of all physician visits, 49% were for the pathology for which an NSAID was prescribed, and 5% were due to NSAID ADRs experienced by 23% of the patients. NSAID ADR occurrence was significantly associated with the number of NSAID prescriptions filled (OR: 1.5; 95% CI: 1.3–1.8). The most common NSAID ADRs were upper abdominal pain in 13% of the patients, heartburn in 9%, and dyspepsia in 2%, while other NSAID ADRs occurred in 2% of the patients. Among all NSAID users, 4% had a GI endoscopic exam, 20% had a specialist consultation, 5% were hospitalised, and 31% had an X-ray. Compared to the patients who did not report any visits due to NSAID ADRs, those with NSAID ADRs were more likely to have a GI endoscopic exam (OR: 13.7; 95% CI: 6.4–29.3), a specialist visit (OR: 2.0: 95% CI: 1.4–2.9), hospitalisation (OR: 2.0; 95% CI: 1.1–3.8), and X-ray (OR: 1.4; 95% CI: 1.0–2.0). <h3>Conclusion</h3> NSAID related adverse drug reactions were relatively common in this group of NSAID users and resulted in the consumption of a considerable amount of healthcare resources, such as physician visits, specialist consultations, diagnostic tests, and hospitalizations.
Trust pays £7m for brain damage from failure to treat baby’s eye infection
Authors: Clare Dyer
Journal: BMJ (2021)

The NHS has agreed to pay more than £7m (€7.9m; $9.6m) in an out of court settlement for failing to treat properly a newborn baby’s eye infection, leaving him with permanent brain damage.

The settlement, which was approved by the High Court, was disclosed on the legal information website Lexology by the boy’s solicitor, Jon Nicholson of the London law firm Anthony Gold. The NHS trust involved is not identified and the boy, who is now an adult and has an anonymity order …
Liver enzyme elevation and acute liver injury are independently associated with adverse clinical outcomes in patients with COVID-19: A territory-wide cohort study of 1,040 patients in Hong Kong
Authors: T. C. F. Yip, G. C. Y. Lui, V. Wong, V. C. Y. Chow, T. H. Y. Ho, T. C. M. Li, Y. K. Tse, D. S. C. Hui, H. L. Y. Chan, G. L. H. Wong
Journal: Hepatology (2020)

Background: Different degrees of liver injury were reported in patients infected by Coronavirus disease 2019 (COVID-19) It is possibly caused by systemic inflammation and adverse drug reactions in severe COVID-19 patients under different medical treatments However, the impact of liver injury on adverse clinical outcomes remains unclear We aimed to examine the impact of liver injury on clinical outcomes in COVID-19 patients Methods: All COVID-19 patients reported to the Department of Health between 23 January 2020 and 1 May 2020 in Hong Kong were identified using an electronic database managed by Hospital Authority, Hong Kong, and retrospectively studied Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2x upper limit of normal (ULN) (i e  80 U/L) Acute liver injury was defined as ALT and/or AST ≥2xULN, with total bilirubin ≥2xULN (i e  38 μmol/L) and/or international normalized ratio (INR) ≥1 7  The primary endpoint was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation, and/or death Results: 1,040 COVID-19 patients were identified  Their mean age was 38±18 years, 560 (53 8%) were male, 4 1% and 0 3% had hepatitis B and C virus infection, respectively;53 (5 1%) were admitted to ICU, 22 (2 1%) received invasive mechanical ventilation, and 4 (0 4%) died Among 816 COVID-19 patients who had serial measurement of liver biochemistries, 184 (22 5%) had ALT/ AST elevation and 15 (1 8%) had acute liver injury Acute liver injury was more common in patients who had hepatitis B/C virus infection than those who did not have (9 4% vs  1 8%, P=0 026) ALT/AST elevation (adjusted odds ratio [aOR] 7 92, 95% CI 4 14-15 14, P<0 001) and acute liver injury (aOR 6 40, 95% CI 1 78-23 07, P=0 005) were independently associated with development of primary endpoint (Table) Use of lopinavirritonavir ± ribavirin + interferon beta (aOR 1 94, 95% CI 1 20- 3 13, P=0 006) and corticosteroids (aOR 3 92, 95% CI 2 14- 7 16, P<0 001) were independently associated with ALT/AST elevation Use of corticosteroids was associated with acute liver injury (aOR 4 76, 95% CI 1 56-14 50, P=0 006), while all 15 patients who developed acute liver injury also usedlopinavir-ritonavir ± ribavirin ± interferon beta Conclusion: ALT/AST elevation and acute liver injury were independently associated with adverse clinical outcomes in COVID-19 patients Use of lopinavir-ritonavir, with or without ribavirin, interferon beta and/or corticosteroids were associated with ALT/AST elevation and acute liver injury in COVID-19 patients
Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study
Authors: José Villar, Robert B. Gunier, Chrystelle O. O. Tshivuila-Matala, Stephen A. Rauch, Francois Nosten, Roseline Ochieng, María C. Restrepo-Méndez, Rose McGready, Fernando C. Barros, Michelle Fernandes, Verena I. Carrara, Cesar G. Victora, Shama Munim, Rachel Craik, Hellen C. Barsosio, Maria Carvalho, James A. Berkley, Leila Cheikh Ismail, Shane A. Norris, Eric O. Ohuma, Alan Stein, Ann Lambert, Adele Winsey, Ricardo Uauy, Brenda Eskenazi, Zulfiqar A. Bhutta, Aris T. Papageorghiou, Stephen H. Kennedy
Journal: Nature Medicine (2021)
The Proportion of SARS-CoV-2 Infections That Are Asymptomatic
Authors: Daniel P. Oran, Eric J. Topol
Journal: Annals of Internal Medicine (2021)

Asymptomatic infection seems to be a notable feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), but the prevalence is uncertain.