tbuckley/cabot-search huggingface dataset:
What has caused the NHS blood tube shortage, and how is it affecting doctors and patients?
Authors: Abi Rimmer
Journal: BMJ (2021)

Becton Dickinson (BD), which manufactures most of the blood tubes used by the NHS, has alerted NHS England and NHS Improvement (NHSE/I) to a global shortage of some of its products. This includes two types of blood tubes: those with a yellow or purple top.

BD says that the covid-19 pandemic created the most unpredictable demand it has seen in the past 70 years. The company says that it has also been difficult for customers to predict the types and quantities of blood tubes they will be using from month to month, which affects manufacturers’ abilities to meet demand. “Adding to the issue are global transportation delays that have resulted in more products being tied up in transportation than is normal, creating additional delays in deliveries,” BD said in a statement. “Raw material suppliers are also challenged to keep up with demand for materials and components.”

In the UK, BD has been authorised to import blood tubes that are approved for use in other regions of the world, including the United States. It plans to deliver nine million of these additional blood tubes to the NHS for immediate distribution. Ahead of this, the tubes were assessed and approved by the Medicines and Healthcare Products …
P-199 Baseline neutrophil to lymphocyte ratio predicts survival in patients with metastatic colorectal cancer treated with cetuximab plus avelumab (CAVE) as a rechallenge strategy
Authors: D. Ciardiello, V. Famiglietti, S. Napolitano, M. Terminiello, C. Borrelli, P. Vitiello, F. Pietrantonio, A. Avallone, N. Normanno, E. Maiello, T. Latiano, C. Cremolini, G. Santabarbara, C. Pinto, D. Santini, L. Esposito, A. Di Liello, T. Troiani, F. Ciardiello, E. Martinelli, G. Martini
Journal: Annals of Oncology (2021)
The association of community mobility with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 330 local UK authorities
Authors: You Li, Xin Wang, Harry Campbell, Harish Nair
Journal: The Lancet Digital Health (2021)

<h2>Summary</h2><h3>Background</h3> Community mobility data have been used to assess adherence to non-pharmaceutical interventions and its impact on SARS-CoV-2 transmission. We assessed the association between location-specific community mobility and the reproduction number (<i>R</i>) of SARS-CoV-2 across UK local authorities. <h3>Methods</h3> In this modelling study, we linked data on community mobility from Google with data on <i>R</i> from 330 UK local authorities, for the period June 1, 2020, to Feb 13, 2021. Six mobility metrics are available in the Google community mobility dataset: visits to retail and recreation places, visits to grocery and pharmacy stores, visits to transit stations, visits to parks, visits to workplaces, and length of stay in residential places. For each local authority, we modelled the weekly change in <i>R</i> (the <i>R</i> ratio) per a rescaled weekly percentage change in each location-specific mobility metric relative to a pre-pandemic baseline period (Jan 3–Feb 6, 2020), with results synthesised across local authorities using a random-effects meta-analysis. <h3>Findings</h3> On a weekly basis, increased visits to retail and recreation places were associated with a substantial increase in <i>R</i> (<i>R</i> ratio 1·053 [99·2% CI 1·041–1·065] per 15% weekly increase compared with baseline visits) as were increased visits to workplaces (<i>R</i> ratio 1·060 [1·046–1·074] per 10% increase compared with baseline visits). By comparison, increased visits to grocery and pharmacy stores were associated with a small but still statistically significant increase in <i>R</i> (<i>R</i> ratio 1·011 [1·005–1·017] per 5% weekly increase compared with baseline visits). Increased visits to parks were associated with a decreased <i>R</i> (<i>R</i> ratio 0·972 [0·965–0·980]), as were longer stays at residential areas (<i>R</i> ratio 0·952 [0·928–0·976]). Increased visits to transit stations were not associated with <i>R</i> nationally, but were associated with a substantial increase in <i>R</i> in cities. An increasing trend was observed for the first 6 weeks of 2021 in the effect of visits to retail and recreation places and workplaces on <i>R</i>. <h3>Interpretation</h3> Increased visits to retail and recreation places, workplaces, and transit stations in cities are important drivers of increased SARS-CoV-2 transmission; the increasing trend in the effects of these drivers in the first 6 weeks of 2021 was possibly associated with the emerging alpha (B.1.1.7) variant. These findings provide important evidence for the management of current and future mobility restrictions. <h3>Funding</h3> Wellcome Trust and Data-Driven Innovation initiative.
Sepsis expands a CD39+ plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity
Authors: Daniele Carvalho Nascimento, Paula Ramos Viacava, Raphael Gomes Ferreira, Marina Alves Damaceno, Annie Rocío Piñeros, Paulo Henrique Melo, Paula Barbim Donate, Juliana Escher Toller-Kawahisa, Daniel Zoppi, Flávio Protásio Veras, Raphael Sanches Peres, Luísa Menezes-Silva, Diego Caetité, Antonio Edson Rocha Oliveira, Ícaro Maia Santos Castro, Gilles Kauffenstein, Helder Imoto Nakaya, Marcos Carvalho Borges, Dario Simões Zamboni, Denise Morais Fonseca, Jonas Augusto Rizzato Paschoal, Thiago Mattar Cunha, Valerie Quesniaux, Joel Linden, Fernando Queíroz Cunha, Bernhard Ryffel, José Carlos Alves-Filho
Journal: Immunity (2021)
COVID-19 associated pulmonary aspergillosis: regional variation in incidence and diagnostic challenges
Authors: Juergen Prattes, Philipp Koehler, Martin Hoenigl, Joost Wauters, Daniele Roberto Giacobbe, Katrien Lagrou, Jon Salmanton-García, Riina Rautemaa-Richardson, Stefan Hatzl, Johan Maertens, Yves Debaveye, Marc Bourgeois, Marijke Reynders, Lynn Rutsaert, Niels Van Regenmortel, Piet Lormans, Simon Feys, Alexander Christian Reisinger, Oliver A. Cornely, Tobias Lahmer, Maricela Valerio, Laurence Delhaes, Kauser Jabeen, Joerg Steinmann, Mathilde Chamula, Matteo Bassetti
Journal: Intensive Care Medicine (2021)
活動性潰瘍性大腸炎患者の無作為化試験におけるホスホジエステラーゼ4の経口阻害剤,アプレミラストの効果【JST・京大機械翻訳】
Authors: Danese Silvio, F Neurath Markus, Kopon Adam, F Zakko Salam, C Simmons Timothy, Fogel Ronald, A Siegel Corey, Panaccione Remo, Zhan Xiaojiang, Usiskin Keith, Chitkara Denesh
Journal: Clinical Gastroenterology and Hepatology (2020)
Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis
Authors: Yvette Robbins, Jay Friedman, Paul E Clavijo, Cem Sievers, Ke Bai, Renee N Donahue, Jeffrey Schlom, Andrew Sinkoe, Houssein Abdul Sater, James L Gulley, Scott Norberg, Christian S Hinrichs, Clint Allen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types.We conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison.Dual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject's own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas.Intact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP.NCT03707587 and NCT02859454.
Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications
Authors: Moritz Reese, Sameer A. Dhayat
Journal: Journal of Hematology & Oncology (2021)

Abstract Pancreatic cancer has the worst prognosis among common tumors which is attributed to its aggressive phenotype, diagnosis at advanced, inoperable stages, and resistance to systemic therapy. Non-coding RNAs (ncRNAs) such as microRNAs, long non-coding RNAs, and circular RNAs have been established as important regulators of gene expression and their deregulation has been implicated in multiple diseases and foremost cancer. In the tumor microenvironment, non-coding RNAs can be distributed among cancer cells, stromal cells, and immune cells via small extracellular vesicles (sEVs), thereby facilitating intercellular communication and influencing major cancer hallmarks such as angiogenesis, evasion of the immune system, and metastatic dissemination. Furthermore, sEV-ncRNAs have shown promising potential as liquid biopsies with diagnostic and prognostic significance. In this review, we summarize the role of sEVs as carriers of ncRNAs and underlying molecular mechanisms in pancreatic cancer. Moreover, we review the potential of sEV-ncRNAs as biomarkers and highlight the suitability of sEVs as delivery vehicles for ncRNA-based cancer therapy.
Recommendations for diagnosis and treatment of methemoglobinemia
Authors: Achille Iolascon, Paola Bianchi, Immacolata Andolfo, Roberta Russo, Wilma Barcellini, Elisa Fermo, Gergely Toldi, Stefano Ghirardello, Davis Rees, Richard Van Wijk, Antonis Kattamis, Patrick G. Gallagher, Noemi Roy, Ali Taher, Razan Mohty, Andreas Kulozik, Lucia De Franceschi, Antonella Gambale, Mariane De Montalembert, Gian Luca Forni, Cornelis L. Harteveld, Josef Prchal
Journal: American Journal of Hematology (2021)

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions.
Considerations of a real life pragmatic clinical trial in adolescent asthma
Authors: Tom Ruffles, Brian Lipworth, Somnath Mukhopadhyay
Journal: European Respiratory Journal (2021)

We appreciate the interest shown by J.F.M. van Boven and co-workers in our study. PACT [1] was first and foremost designed as a pragmatic randomised controlled trial (RCT) reflecting current UK primary care practice. While addition of controller treatment for those in the personalised care group with poor control was guided by the study algorithm, the decisions with respect to monotherapy versus combination therapy, inhaler type and use of a spacer was down to the discretion of the participant's primary care team. A pragmatic trial design was used to elucidate potential effects of genotype directed asthma prescribing in a real life primary care setting <https://bit.ly/2PpYavS>
Integrin and syndecan binding peptide-conjugated alginate hydrogel for modulation of nucleus pulposus cell phenotype
Authors: Xiaohong Tan, Era Jain, Marcos N. Barcellona, Evan Morris, Sydney Neal, Munish C. Gupta, Jacob M. Buchowski, Michael Kelly, Lori A. Setton, Nathaniel Huebsch
Journal: Biomaterials (2021)
Abstract 11495: HBI-3000: A Novel Drug for Conversion of Atrial Fibrillation - Phase 1 Study Results
Authors: Jay W Mason, Gary T Elliott, Suzanne J Romano, Boaz Mendzelevski, Robin Allgren, Mireille Gillings, Denis Roy
Journal: Circulation (2019)

Background: HBI-3000 is a multi-ion channel blocker with in vitro inhibitory effects on INa-Peak, INa-Late, ICa,L and IKr being developed by HUYA Bioscience International for the conversion of rece...
Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
Authors: Bishal Gyawali, Benjamin N Rome, Aaron S Kesselheim
Journal: BMJ (2021)

To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines.Retrospective observational study.FDA and National Comprehensive Cancer Network (NCCN) reports.Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials.Regulatory outcomes, including withdrawal, conversion to regular approval, and no action.18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.
Regulator of G‐protein signaling 14 protects the liver from ischemia–reperfusion injury by suppressing TGF‐β‐activated kinase 1 activation
Authors: Jia‐Kai Zhang, Ming‐Jie Ding, Hui Liu, Ji‐Hua Shi, Zhi‐Hui Wang, Pei‐Hao Wen, Yi Zhang, Bing Yan, Dan‐Feng Guo, Xiao‐Dan Zhang, Ruo‐Lin Tao, Zhi‐Ping Yan, Yan Zhang, Zhen Liu, Wen‐Zhi Guo, Shui‐Jun Zhang
Journal: Hepatology (2021)

Abstract Background and Aims Hepatic ischemia–reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Regulator of G‐protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates the G‐protein and mitogen‐activated protein kinase (MAPK) signaling pathways. However, the role of RGS14 in hepatic IRI remains unclear. Approach and Results We found that RGS14 expression increased in mice subjected to hepatic ischemia–reperfusion (IR) surgery and during hypoxia reoxygenation in hepatocytes. We constructed global RGS14 knockout ( RGS14 ‐KO) and hepatocyte‐specific RGS14 transgenic (RGS14‐TG) mice to establish 70% hepatic IRI models. Histological hematoxylin and eosin staining, levels of alanine aminotransferase and aspartate aminotransferase, expression of inflammatory factors, and apoptosis were used to assess liver damage and function in these models. We found that RGS14 deficiency significantly aggravated IR‐induced liver injury and activated hepatic inflammatory responses and apoptosis in vivo and in vitro. Conversely, RGS14 overexpression exerted the opposite effect of the RGS14‐deficient models. Phosphorylation of TGF‐β‐activated kinase 1 (TAK1) and its downstream effectors c‐Jun N‐terminal kinase (JNK) and p38 increased in the liver tissues of RGS14 ‐KO mice but was repressed in those of RGS14‐TG mice. Furthermore, inhibition of TAK1 phosphorylation rescued the effect of RGS14 deficiency on JNK and p38 activation, thus blocking the inflammatory responses and apoptosis. Conclusions RGS14 plays a protective role in hepatic IR by inhibiting activation of the TAK1–JNK/p38 signaling pathway. This may be a potential therapeutic strategy for reducing incidences of hepatic IRI in the future.
Par-4 Overexpression Impedes Leukemogenesis in the Eµ-TCL1 Leukemia Model
Authors: Joseph Thomas Greene, Rahul Ramaswamy, Mary K McKenna, Rajeswaran Mani, Frank Frissora, Ronni Wasmuth, Minh Tran, Xiaokui Mo, Carlo M. Croce, Vivek Rangnekar, John C. Byrd, Subbarao Bondada, Natarajan Muthusamy
Journal: Blood (2017)
Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double‐blind randomized controlled trial
Authors: Abraham Zangen, Hagar Moshe, Diana Martinez, Noam Barnea‐Ygael, Tanya Vapnik, Alexander Bystritsky, Walter Duffy, Doron Toder, Leah Casuto, Moran Lipkinsky Grosz, Edward V. Nunes, Herbert Ward, Aron Tendler, David Feifel, Oscar Morales, Yiftach Roth, Dan V. Iosifescu, Jaron Winston, Theodore Wirecki, Ahava Stein, Frederic Deutsch, Xingbao Li, Mark S. George
Journal: World Psychiatry (2021)

Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double‐blind RCT in 262 chronic smokers meeting DSM‐5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat­eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue‐induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four‐week continuous quit rate (CQR) until Week 18 in the intent‐to‐treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent‐to‐treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X 2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X 2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok­ing cessation for adults.
The conserved long non-coding RNA <i>CARMA</i> regulates cardiomyocyte differentiation
Authors: Maryam Kay, Bahram M Soltani, Mohamed Nemir, Parisa Aghagolzadeh, Iole Pezzuto, Panagiotis Chouvardas, Francesco Ruberto, Fatemeh Movahedi, Hassan Ansari, Hossein Baharvand, Thierry Pedrazzini
Journal: Cardiovascular Research (2021)

Abstract Aims Production of functional cardiomyocytes from pluripotent stem cells requires tight control of the differentiation process. Long non-coding RNAs (lncRNAs) exert critical regulatory functions in cell specification during development. In this study, we designed an integrated approach to identify lncRNAs implicated in cardiogenesis in differentiating human embryonic stem cells (ESCs). Methods and results We identified CARMA (CARdiomyocyte Maturation-Associated lncRNA), a conserved lncRNA controlling cardiomyocyte differentiation and maturation in human ESCs. CARMA is located adjacent to MIR-1-1HG, the host gene for two cardiogenic miRNAs: MIR1-1 and MIR-133a2, and transcribed in an antisense orientation. The expression of CARMA and the miRNAs are negatively correlated, and CARMA knockdown increases MIR1-1 and MIR-133a2 expression. In addition, CARMA possesses MIR-133a2 binding sites, suggesting the lncRNA could be also a target of miRNA action. Upon CARMA down-regulation, MIR-133a2 target protein-coding genes are coordinately down-regulated. Among those, we found RBPJ, the gene encoding the effector of the NOTCH pathway. NOTCH has been shown to control a binary cell fate decision between the mesoderm and the neuroectoderm lineages, and NOTCH inhibition leads to enhanced cardiomyocyte differentiation at the expense of neuroectodermal derivatives. Interestingly, two lncRNAs, linc1230 and linc1335, which are known repressors of neuroectodermal specification, were found up-regulated upon Notch1 silencing in ESCs. Forced expression of either linc1230 or linc1335 improved ESC-derived cardiomyocyte production. These two lncRNAs were also found up-regulated following CARMA knockdown in ESCs. Conclusions Altogether, these data suggest the existence of a network, implicating three newly identified lncRNAs, the two myomirs MIR1-1 and MIR-133a2 and the NOTCH signalling pathway, for the coordinated regulation of cardiogenic differentiation in ESCs.
Modeling human hypertrophic scars with 3D preformed cellular aggregates bioprinting
Authors: Yao Bin, Zhu Dongzhen, Cui Xiaoli, Enhe jirigala, Song Wei, Li Zhao, Hu Tian, Zhu Ping, Li Jianjun, Wang Yuzhen, Zhang Yijie, Fu Xiaobing, Huang Sha
Journal: Bioactive Materials (2021)

The therapeutic interventions of human hypertrophic scars (HHS) remain puzzle largely due to the lack of accepted models. Current HHS models are limited by their inability to mimic native scar architecture and associated pathological microenvironments. Here, we create a 3D functional HHS model by preformed cellular aggregates (PCA) bioprinting, firstly developing bioink from scar decellularized extracellular matrix (ECM) and alginate-gelatin (Alg-Gel) hydrogel with suitable physical properties to mimic the microenvironmental factors, then pre-culturing patient-derived fibroblasts in this bioink to preform the topographic cellular aggregates for sequent printing. We confirm the cell aggregates preformed in bioink displayed well defined aligned structure and formed functional scar tissue self-organization after bioprinting, hence showing the potential of creating HHS models. Notably, these HHS models exhibit characteristics of early-stage HHS in gene and protein expression, which significantly activated signaling pathway related to inflammation and cell proliferation, and recapitulate in vivo tissue dynamics of scar forming. We also use the in vitro and in vivo models to define the clinically observed effects to treatment with concurrent anti-scarring drugs, and the data show that it can be used to evaluate the potential therapeutic target for drug testing. The ideal humanized scar models we present should prove useful for studying critical mechanisms underlying HHS and to rapidly test new drug targets and develop patient-specific optimal therapeutic strategies in the future.