tbuckley/cabot-search huggingface dataset:
Preclinical evaluation of liposome-supported peritoneal dialysis for the treatment of hyperammonemic crises
Authors: Simon Matoori, Vincent Forster, Valentina Agostoni, Regula Bettschart-Wolfensberger, Rima Nadine Bektas, Beat Thöny, Johannes Häberle, Jean-Christophe Leroux, Meriam Kabbaj
Journal: Journal of Controlled Release (2020)

Liposome-supported peritoneal dialysis (LSPD) with transmembrane pH-gradient liposomes was previously shown to enhance ammonia removal in cirrhotic rats and holds promise for the treatment of hyperammonemic crises-associated disorders. The main objective of this work was to conduct the preclinical evaluation of LSPD in terms of pharmacokinetics, ammonia uptake, and toxicology to seek regulatory approval for a first-in-human study. The formulation containing citric acid-loaded liposomes was administered intraperitoneally at two different doses once daily for ten days to healthy minipigs. It was also tested in a domestic pig model of hyperammonemia. The pharmacokinetics of citric acid and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was linear following intraperitoneal administration of medium and high dose. There was no systemic accumulation following daily doses over ten days. The systemic exposure to phospholipids remained low. Furthermore, the liposome-containing peritoneal fluid contained significantly higher ammonia levels than the liposome-free control, demonstrating efficient ammonia sequestration in the peritoneal space. This was indeed confirmed by the ability of LSPD to decrease plasmatic ammonia levels in artificially induced hyperammonemic pigs. LSPD was well tolerated, and no complement activation-related pseudoallergy reactions were observed. The safety profile, the linear pharmacokinetics of citric acid following repeated administrations of LSPD as well as the linear dose-dependent ammonia sequestration in the peritoneal space provide a strong basis for the clinical investigation of LSPD.
THU0216 Nsaids self-prescription as a cause of upper gastrointestinal hemorraghe
Authors: J Rosas, E Server, J Ena, A Romero, J Valverde, A García, C Quílez, J Vázquez, MT Torres, B Simons
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Non-steroidal anti-inflammatory drugs (NSAIDs) are compounds easily to acquire over the counter that are extensively used for symptomatic relieve of pain of any origin and for platelet antiaggregation purposes. <h3>Objectives</h3> To describe the epidemiology of NSAIDs usage and its association with upper gastrointestinal hemorraghe in a community hospital from Spain. <h3>Methods</h3> We prospectively studied the clinical usage, indication, duration, dose, type of NSAID therapy, presence of NSAIDs self prescription and use of concomitant drugs in all patients admitted to the hospital with upper gastrointestinal haemorrhage from October-1999 to November-2000. All patient underwent endoscopy to assess the type of gastroscopic lesion and the presence of Helicobacter pylori. Requirements of blood transfusion and surgery were also noted. <h3>Results</h3> A total 63 (29%) out of 216 patients admitted with upper gastrointestinal haemorrhage were using NSAIDs (60% aspirin, 16% piroxicam, 13% diclofenac, 6% combined and 5% other) during a median of 7.5 days (range 1- &gt;100 days). Median patients´ age was 65 years (range 18–90). NSAIDs were prescribed for pain relieve (75%), platelet anti-aggregation (19%) or both (6%). Indication for prescription was done by rheumathology consultants (0%), general practitioners (25%), other consultants (33%) and self-prescribed (41%). Location of lesions at endoscopy were: esophageal (5%), gastric (35%), duodenal (43%) and, multiple lesions (17%). Helicobacter pylori was present in 28 (70%) out of 40 samples. A total of 44 (70%) patients had at least one risk factor for NSAIDs gastropathy of whom only 2 (4%) were receiving prophylaxis with protein pump inhibitors and 1 (2%) with H2-blockers. NSAIDs gastrointestional haemorrhage accounted for a total of 346 admission days, 40 (63%) patients needed blood transfusion and one (1%) suffered surgery. <h3>Conclusion</h3> Self-prescription is a common cause of NSAIDs gastrointestinal haemorrhage. Only a minor proportion of patients with risk factors for NSAIDs gastropathy receive appropriate prophylaxis with protein pump inhibitors.
Reinvigorating exhausted CD8<sup>+</sup> cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy
Authors: Md Amir Hossain, Guilai Liu, Beiying Dai, Yaxuan Si, Qitao Yang, Junaid Wazir, Lutz Birnbaumer, Yong Yang
Journal: Medicinal Research Reviews (2020)

Abstract Immunotherapy has revolutionized the treatment of cancer in recent years and achieved overall success and long‐term clinical benefit in patients with a wide variety of cancer types. However, there is still a large proportion of patients exhibiting limited or no responses to immunotherapeutic strategy, some of which were even observed with hyperprogressive disease. One major obstacle restricting the efficacy is that tumor‐reactive CD8 + T cells, which are central for tumor control, undergo exhaustion, and lose their ability to eliminate cancer cells after infiltrating into the strongly immunosuppressive tumor microenvironment. Thus, as a potential therapeutic rationale in the development of cancer immunotherapy, targeting or reinvigorating exhausted CD8 + T cells has been attracting much interest. Hitherto, both intrinsic and extrinsic mechanisms that govern CD8 + T‐cell exhaustion have been explored. Specifically, the transcriptional and epigenetic landscapes have been depicted utilizing single‐cell RNA sequencing or mass cytometry (CyTOF). In addition, cellular metabolism dictating the tumor‐infiltrating CD8 + T‐cell fate is currently under investigation. A series of clinical trials are being carried out to further establish the current strategies targeting CD8 + T‐cell exhaustion. Taken together, despite the proven benefit of immunotherapy in cancer patients, additional efforts are still needed to fully circumvent limitations of exhausted T cells in the treatment. In this review, we will focus on the current cellular and molecular understanding of metabolic changes, epigenetic remodeling, and transcriptional regulation in CD8 + T‐cell exhaustion and describe hypothetical treatment approaches based on immunotherapy aiming at reinvigorating exhausted CD8 + T cells.
Development and Validation of an Automated Diabetic Retinopathy Screening Tool for Primary Care Setting
Authors: Alauddin Bhuiyan, Arun Govindaiah, Avnish Deobhakta, Meenakashi Gupta, Richard Rosen, Sophia Saleem, R. Theodore Smith
Journal: Diabetes Care (2020)

We report the construction of a fully automated artificial intelligence deep learning (DL) software on a secure Health Insurance Portability and Accountability Act–compliant cloud-based platform for effective and efficient screening of referable and nonreferable diabetic retinopathy (DR) in the primary care setting. DR is one of the leading causes of blindness in the U.S. and other developed countries. Early detection is the key for prevention. Currently, screening for DR is done by ophthalmologists or optometrists with limited catchment areas and also requires time-consuming referral. Many patients (some studies suggest almost one out of three) do not get these exams (1).

The critical goal is the screening of “referable” DR for referral to an ophthalmologist. A 5-point scale (2) (no DR and mild, moderate, severe, and proliferative DR) may be used for grading DR based on the presence and extent of microaneurysms, exudates, hemorrhages, and other abnormalities. By definition, no DR and mild DR are considered nonreferable, and the other categories are considered referable. Previous automated DR screening techniques are of varying accuracy and performance, but recently DL approaches have had greater success.

DL refers to a class of machine learning techniques that learns features directly from images without feature labels and usually requires very large training data sets …
Central Nervous System Cancers Clinical Practice Guidelines in Oncology
Authors: Steven S Brem, Philip J Bierman, Peter Black, Deborah T Blumenthal, Henry Brem, Marc C Chamberlain, Ennio A Chiocca, Lisa M DeAngelis, Robert A Fenstermaker, Howard A Fine, Allan Friedman, Jon Glass, Stuart A Grossman, Amy B Heimberger, Larry Junck, Victor Levin, Jay J Loeffler, Moshe H Maor, Ashwatha Narayana, Herbert B Newton, Alessandro Olivi, Jana Portnow, Michael Prados, Jeffrey J Raizer, Steven S Rosenfeld, Dennis C Shrieve, Allen K Sills, Alexander M Spence, Frank D Vrionis
Journal: Journal of the National Comprehensive Cancer Network (2005)

In the year 2005, an estimated 18,500 new cases of primary brain and nervous system neoplasms will be diagnosed in the United States. These tumors will be responsible for approximately 12,760 deaths. The incidence of primary malignant brain tumors has been increasing over the past 25 years, especially in elderly persons (rates are increasing at about 1.2% each year). Metastatic disease to the central nervous system (CNS) occurs much more frequently, with an incidence about 10 times that of primary brain tumors. It is estimated between 20% and 40% of patients with systemic cancer will develop brain metastases. For the most recent version of the guidelines, please visit NCCN.org
The antitumor effect of orally active heat shock protein 90 Inhibitor, 17-DMAG, on the growth of gefitinib-resistant non-small cell lung cancer
Authors: T. Kubo, N. Kobayashi, M. Jida, T. Hayashi, H. Yamamoto, H. Otani, K. Kiura, Y. Sano, S. Toyooka
Journal: Journal of Clinical Oncology (2009)

e22064 Background: It has been reported that NSCLC cell lines with activating mutations of EGFRgene were significantly sensitive to Heat Shock Protein 90 (Hsp 90 ) ihibitors regardless of the secondary T790M mutation. Methods: We examined the antitumor effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), the orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. Results: In MTS assay, the IC 50 values for 3 cell lines with EGFR mutation (PC-9, RPC-9, and NCI-H1975) ranged from 0.15 to 0.28 μM. RPC-9 is a gefitinib-resistant lung cancer cell line with the secondary T790M mutation established from PC-9. By contrast, those of 7 EGFR-wild type cell lines ranged from 1.63 to 28.5 μM. Western blot analysis revealed that mutant EGFRs were more readily depleted than wild-type EGFRs after the treatment of 17-DMAG. Furthermore, expression of phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 was depleted after exposure to low concentrations of 17-DMAG in EGFR-mutant cells. Celeaved PARP expression confirmed apoptosis in response to 17-DMAG in EGFR-mutant cells. In animal models, 17-DMAG significantly reduced the growth of EGFR-mutant cell lines PC-9 and RPC-9 compared with controls and induced degradation of mutant EGFR. In contrast, 17-DMAG did not inhibit the growth of EGFR wild type cell lines compared with controls. Conclusions: These results suggested that 17-DMAG could become a novel therapeutic agent for patients with lung tumors expressing mutant EGFR and having developed clinical resistance to gefitinib. No significant financial relationships to disclose.
Geographically widespread invasive meningococcal disease caused by a ciprofloxacin resistant non-groupable strain of the ST-175 clonal complex
Authors: Laura Willerton, Jay Lucidarme, Helen Campbell, Dominique A Caugant, Heike Claus, Susanne Jacobsson, Shamez N Ladhani, Paula Mölling, Arianna Neri, Paola Stefanelli, Muhamed-Kheir Taha, Ulrich Vogel, Ray Borrow
Journal: Journal of Infection (2020)
AB0185 Evaluation of physical capacity and disability in osteoporotic women
Authors: I Lombardi Junior, LM Oliveira, CR Monteiro, YQ Confessor, TL Barros, J Natour
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The vertebral osteoporotic fractures result in increased kyphosis angle. This alteration could led to disturbance in physical capacity. <h3>Objectives</h3> Our objective was to evaluate the physical capacity and disability in a group of osteoporotic patients. <h3>Methods</h3> Fifteen women with osteoporosis and vertebral fracture (G1), 20 women with osteoporosis without vertebral fracture (G2) and 20 normal women (G3) were selected. The variables of physical capacity were measured in the belt conveyor. The patients stayed 4 min in standing quietly, 4 min walking at 3 Km/h and 10 min walking at 4 Km/h. It was also applied the questionnary SF-36. <h3>Results</h3> Our results showed that women with osteoporosis and vertebral fracture had increased kyphosis angle (median = 60 degrees) and the G2 was 43.5 degrees and G3 was 37 degrees. G1 showed oxygen consumption (VO2 (Kg)), METS and energy expenditure (Kcal/h) in standing quietly bigger than G2 (G1 vs. G2, p = 0.016; p = 0.017 and p = 0.02, respectively). There wasn’t significant difference in the energy expenditure during the walking between three groups. The energy expenditure during walking at 3 Km/h and at 4 Km/h, showed correlation with thoracic kyphosis in G1 (p = 0.01 and p = 0.017, respectively). It wasn`t find difference in SF-36 between three groups. <h3>Conclusion</h3> Energy expenditure showed correlation with the angle of thoracic kyphosis. Patients with or without osteoporosis had the same energy expenditure during the walking. The SF-36 score was similar between three groups.
Why do tendon researchers overlook the patient’s psychological state? The review with no papers
Authors: Seán Mc Auliffe, Kieran O'Sullivan, Rod Whiteley, Vasileios Korakakis
Journal: British Journal of Sports Medicine (2020)

Exercise or loading interventions remain the conservative treatment of choice in the management of tendinopathy.1 However, as many as 60% of individuals experience continued symptoms, while up to a quarter of patients experiencing symptoms 10 years after treatment.2

What might explain these rather sobering outcomes? We opine that given the complex and often persistent nature of tendinopathy, addressing other factors in addition to exercise variables may prove beneficial. We focus here on the potential role of psychological factors.

Psychological factors have been implicated in many other musculoskeletal disorders, either as prognostic factors,3 as treatment effect modifiers4 or as mediators of recovery.5 As tendinopathy has been shown to be associated with psychological distress and poor quality of life,6 7 measuring psychological factors in randomised controlled trials (RCTs) of exercise would appear justifiable. This does not …
Abstract 17256: Cardiovascular Complications Related to Zika Virus
Authors: Victor G Becerra Gonzales, Paola Lichtenberger, Joel Fishman, Yoel Siegel, Eduard Ghersin, Barry E Hurwitz, Claudia Martinez
Journal: Circulation (2019)

Introduction: In 2016, the WHO declared Zika outbreak a Global Public Health Emergency and Florida was one of the most affected states. Zika virus is a flavivirus that manifests with systemic infec...
Acute Cardiovascular Events Associated With Influenza in Hospitalized Adults
Authors: Eric J. Chow, Melissa A. Rolfes, Alissa O'Halloran, Evan J. Anderson, Nancy M. Bennett, Laurie Billing, Shua Chai, Elizabeth Dufort, Rachel Herlihy, Sue Kim, Ruth Lynfield, Chelsea McMullen, Maya L. Monroe, William Schaffner, Melanie Spencer, H. Keipp Talbot, Ann Thomas, Kimberly Yousey-Hindes, Carrie Reed, Shikha Garg
Journal: Annals of Internal Medicine (2020)

Background: Influenza may contribute to the burden of acute cardiovascular events during annual influenza epidemics. Objective: To examine acute cardiovascular events and determine risk factors for acute heart failure (aHF) and acute ischemic heart disease (aIHD) in adults with a hospitalization associated with laboratory-confirmed influenza. Design: Cross-sectional study. Setting: U.S. Influenza Hospitalization Surveillance Network during the 2010-to-2011 through 2017-to-2018 influenza seasons. Participants: Adults hospitalized with laboratory-confirmed influenza and identified through influenza testing ordered by a practitioner. Measurements: Acute cardiovascular events were ascertained using discharge codes from the International Classification of Diseases (ICD), Ninth Revision, Clinical Modification, and ICD, 10th Revision. Age, sex, race/ethnicity, tobacco use, chronic conditions, influenza vaccination, influenza antiviral medication, and influenza type or subtype were included as exposures in logistic regression models, and marginal adjusted risk ratios and 95% CIs were estimated to describe factors associated with aHF or aIHD. Results: Among 89 999 adults with laboratory-confirmed influenza, 80 261 had complete medical record abstractions and available ICD codes (median age, 69 years [interquartile range, 54 to 81 years]) and 11.7% had an acute cardiovascular event. The most common such events (non–mutually exclusive) were aHF (6.2%) and aIHD (5.7%). Older age, tobacco use, underlying cardiovascular disease, diabetes, and renal disease were significantly associated with higher risk for aHF and aIHD in adults hospitalized with laboratory-confirmed influenza. Limitation: Underdetection of cases was likely because influenza testing was based on practitioner orders. Acute cardiovascular events were identified by ICD discharge codes and may be subject to misclassification bias. Conclusion: In this population-based study of adults hospitalized with influenza, almost 12% of patients had an acute cardiovascular event. Clinicians should ensure high rates of influenza vaccination, especially in those with underlying chronic conditions, to protect against acute cardiovascular events associated with influenza. Primary Funding Source: Centers for Disease Control and Prevention.
COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study
Authors: Jessica J Manson, Colin Crooks, Meena Naja, Amanda Ledlie, Bethan Goulden, Trevor Liddle, Emon Khan, Puja Mehta, Lucia Martin-Gutierrez, Kirsty E Waddington, George A Robinson, Liliana Ribeiro Santos, Eve McLoughlin, Antonia Snell, Christopher Adeney, Ina Schim van der Loeff, Kenneth F Baker, Christopher J A Duncan, Aidan T Hanrath, B Clare Lendrem, Anthony De Soyza, Junjie Peng, Hajar J'Bari, Mandy Greenwood, Ellie Hawkins, Hannah Peckham, Michael Marks, Tommy Rampling, Akish Luintel, Bryan Williams, Michael Brown, Mervyn Singer, Joe West, Elizabeth C Jury, Matthew Collin, Rachel S Tattersall
Journal: The Lancet Rheumatology (2020)
Efficacy of Selpercatinib in <i>RET</i> Fusion–Positive Non–Small-Cell Lung Cancer
Authors: Alexander Drilon, Geoffrey R. Oxnard, Daniel S.W. Tan, Herbert H.F. Loong, Melissa Johnson, Justin Gainor, Caroline E. McCoach, Oliver Gautschi, Benjamin Besse, Byoung C. Cho, Nir Peled, Jared Weiss, Yu-Jung Kim, Yuichiro Ohe, Makoto Nishio, Keunchil Park, Jyoti Patel, Takashi Seto, Tomohiro Sakamoto, Ezra Rosen, Manisha H. Shah, Fabrice Barlesi, Philippe A. Cassier, Lyudmila Bazhenova, Filippo De Braud, Elena Garralda, Vamsidhar Velcheti, Miyako Satouchi, Kadoaki Ohashi, Nathan A. Pennell, Karen L. Reckamp, Grace K. Dy, Jürgen Wolf, Benjamin Solomon, Gerald Falchook, Kevin Ebata, Michele Nguyen, Binoj Nair, Edward Y. Zhu, Luxi Yang, Xin Huang, Elizabeth Olek, S. Michael Rothenberg, Koichi Goto, Vivek Subbiah
Journal: New England Journal of Medicine (2020)

RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
Weight Management and Healthy Lifestyles—Reply
Authors: Solja T. Nyberg, Archana Singh-Manoux, Mika Kivimäki
Journal: JAMA Internal Medicine (2020)

Solja T. Nyberg, PhD; Archana Singh-Manoux, PhD; Jaana Pentti, MSc; Ida E. H. Madsen, PhD; Severine Sabia, PhD; Lars Alfredsson, PhD; Jakob B. Bjorner, MD; Marianne Borritz, PhD; Hermann Burr, PhD; Marcel Goldberg, MD; Katriina Heikkilä, PhD; Markus Jokela, PhD; Anders Knutsson, PhD; Tea Lallukka, PhD; Joni V. Lindbohm, MD; Martin L. Nielsen, PhD; Maria Nordin, PhD; Tuula Oksanen, MD; Jan H. Pejtersen, PhD; Ossi Rahkonen, PhD; Reiner Rugulies, PhD; Martin J. Shipley, MSc; Pyry N. Sipilä, MD; Sari Stenholm, PhD; Sakari Suominen, PhD; Jussi Vahtera, MD; Marianna Virtanen, PhD; Hugo Westerlund, PhD; Marie Zins, MD; Mark Hamer, PhD; G. David Batty, DSc; Mika Kivimäki, PhD
Covid-19: MPs launch legal action against government over failure to disclose details of PPE contracts
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Three MPs and the Good Law Project have launched legal action against the UK government over what they allege is a “persistent and unlawful” failure to disclose details of huge sums of money spent on contracts for personal protective equipment.

The government has approved £15bn (€16.6bn; $19.6bn) for procuring PPE for public sector staff since the start of the covid-19 pandemic.1 But figures compiled by the data provider Tussell show that details of only £2.68bn of PPE spending have been made public,2 while further analysis shows persistent breaches of the requirement to publish information within 30 days.

The claimants argue that the government is in breach of legal regulations …