tbuckley/cabot-search huggingface dataset:
T cell protein tyrosine phosphatase protects intestinal barrier function by restricting epithelial tight junction remodeling
Authors: Ronald R. Marchelletta, Moorthy Krishnan, Marianne R. Spalinger, Taylaur W. Placone, Rocio Alvarez, Anica Sayoc-Becerra, Vinicius Canale, Ali Shawki, Young Su Park, Lucas H.P. Bernts, Stephen Myers, Michel L. Tremblay, Kim E. Barrett, Evan Krystofiak, Bechara Kachar, Dermot P.B. McGovern, Christopher R. Weber, Elaine M. Hanson, Lars Eckmann, Declan F. McCole
Journal: Journal of Clinical Investigation (2021)

Genome-wide association studies revealed that loss-of-function mutations in protein tyrosine phosphatase non-receptor type 2 (PTPN2) increase the risk of developing chronic immune diseases, such as inflammatory bowel disease (IBD) and celiac disease. These conditions are associated with increased intestinal permeability as an early etiological event. The aim of this study was to examine the consequences of deficient activity of the PTPN2 gene product, T cell protein tyrosine phosphatase (TCPTP), on intestinal barrier function and tight junction organization in vivo and in vitro. Here, we demonstrate that TCPTP protected against intestinal barrier dysfunction induced by the inflammatory cytokine IFN-γ by 2 mechanisms: it maintained localization of zonula occludens 1 and occludin at apical tight junctions and restricted both expression and insertion of the cation pore-forming transmembrane protein, claudin-2, at tight junctions through upregulation of the inhibitory cysteine protease, matriptase. We also confirmed that the loss-of-function PTPN2 rs1893217 SNP was associated with increased intestinal claudin-2 expression in patients with IBD. Moreover, elevated claudin-2 levels and paracellular electrolyte flux in TCPTP-deficient intestinal epithelial cells were normalized by recombinant matriptase. Our findings uncover distinct and critical roles for epithelial TCPTP in preserving intestinal barrier integrity, thereby proposing a mechanism by which PTPN2 mutations contribute to IBD.
Reply to “D” matters in recombinant AAV packaging
Authors: Jakob Shoti, Keyun Qing, Arun Srivastava
Journal: Molecular Therapy (2021)

We read with great interest the Letter to the Editor entitled ‘“D” Matters in Recombinant AAV packaging’ by Zhang et al., 1 Zhang J. Guo P. Xu Y. Mulcrone P.L. Samulski R.J. Xiao W. “D” matters in recombinant AAV DNA packaging. Mol. Ther. 2021; 29: 1937-1939 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar which was recently published in Molecular Therapy. These authors have made major contributions to the adeno-associated virus (AAV) field in the past, and the data presented in their Letter to the Editor are a fine example of their thoughtful analysis of the role of the D-sequence within the AAV inverted terminal repeats (ITRs) in AAV genome packaging. However, in contrast to the critical role that the D-sequence plays in the rescue, replication, and packaging of the single-stranded (ss) wild-type (WT) AAV genomes, based on their data with self-complementary (sc) recombinant AAV (rAAV) vectors containing a reporter gene, Zhang et al. 1 Zhang J. Guo P. Xu Y. Mulcrone P.L. Samulski R.J. Xiao W. “D” matters in recombinant AAV DNA packaging. Mol. Ther. 2021; 29: 1937-1939 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar concluded that the D-sequence does not matter much in the packaging of scAAV vectors. We wish to further emphasize the following important distinctions between the processing of scAAV vector versus the ss WT-AAV genomes. (1)Replication of the WT-AAV genome and production of progeny virions during a natural course of infection in the presence of a helper virus may not precisely mimic the rescue, replication, and packaging of the WT-AAV genome from a recombinant plasmid following DNA-mediated transfection. (2)Rescue, replication, and packaging of the WT-ssAAV genome from a recombinant plasmid, and those of either a ssAAV or a scAAV vector genome, are likely to be different following DNA-mediated transfection in the presence of helper virus genes or in helper virus-infected cells.
Therapeutic potential of pro-resolving mediators in diabetic kidney disease
Authors: Tanwi Vartak, Catherine Godson, Eoin Brennan
Journal: Advanced Drug Delivery Reviews (2021)

Renal microvascular disease associated with diabetes [Diabetic kidney disease - DKD] is the leading cause of chronic kidney disease. In DKD, glomerular basement membrane thickening, mesangial expansion, endothelial dysfunction, podocyte cell loss and renal tubule injury contribute to progressive glomerulosclerosis and tubulointerstitial fibrosis. Chronic inflammation is recognized as a major pathogenic mechanism for DKD, with resident and circulating immune cells interacting with local kidney cell populations to provoke an inflammatory response. The onset of inflammation is driven by the release of well described proinflammatory mediators, and this is typically followed by a resolution phase. Inflammation resolution is achieved through the bioactions of endogenous specialized pro-resolving lipid mediators (SPMs). As our understanding of SPMs advances 'resolution pharmacology' based approaches using these molecules are being explored in DKD.
Understanding neutralising antibodies against SARS-CoV-2 and their implications in clinical practice
Authors: Natalie Yan-Lin Pang, Alexander Shao-Rong Pang, Vincent T. Chow, De-Yun Wang
Journal: Military Medical Research (2021)

Abstract SARS-CoV-2 is a newly identified member of the coronavirus family that has caused the Coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2 has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19 cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies (NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response, particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting—from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.
Primary care backlog will add to urgent care pressures over time
Authors: Clifford W Jones
Journal: BMJ (2021)

Oliver discusses whether separating the NHS into “hot” (urgent) and “cold” (elective) inpatient sites might work.1 But what about hot and cold primary care?

The challenge is trying to balance urgent care with management of long term conditions. I really struggle with this. The current demand for urgent care makes me worry about what I might be missing—the person with serious pathology who waits because “I …
Booster-dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series
Authors: Caoilfhionn M Connolly, Mayan Teles, Sarah Frey, Brian J Boyarsky, Jennifer L Alejo, William A Werbel, Jemima Albayda, Lisa Christopher-Stine, Jacqueline Garonzik-Wang, Dorry L Segev, Julie J Paik
Journal: Annals of the Rheumatic Diseases (2021)

An attenuated humoral response to SARS-CoV-2 vaccination has been observed in some patients with autoimmune disease,1 2 and immunosuppressed status has been associated with an increased risk of COVID-19 infection despite vaccination.3 Recent studies have demonstrated enhanced humoral response to third-dose SARS-CoV-2 vaccination in immunosuppressed transplant patients,4 5 but the immunogenicity of booster vaccination in other immunosuppressed populations is unknown. Thus, we sought to describe the humoral response in patients with autoimmune disease who received a booster SARS-CoV-2 vaccine.

Using our prospective cohort of patients with autoimmune disease,5 we included patients who reported receipt of a single booster dose of SARS-CoV-2 mRNA or adenovirus vector vaccine between 10 April and 11 June 2021. We observed serial anti-spike antibody responses among these participants.

A total of 18 participants received a booster SARS-CoV-2 vaccine dose (table 1). Most (13/18) were women with median (IQR) age of 55 (44–63) years. The most common autoimmune diagnoses included myositis (n=6) and inflammatory arthritis (n=3). Most (14/18) were on antimetabolite therapy; mycophenolate was the most commonly reported immunosuppressive therapy (n=8), with a median (IQR) daily dose of 3000 mg (2500–3000 mg). Participants completed initial vaccination with either Pfizer (n=8), Moderna (n=6) or Johnson & Johnson/Janssen (J&J) Ad26.COV2.S (n=4).

View this table:

Table 1 
Vaccines administered, autoimmune diagnoses, immunosuppression and peri-vaccination management with longitudinal anti-spike antibody responses



Anti-spike antibodies, evaluated via Roche Elecsys anti-RBD pan-Ig were negative in 10 participants (anti-RBD <0.8 U/mL) and low-positive …
Recommended Primary Outcomes for Clinical Trials Evaluating Hemostatic Agents in Patients With Intracranial Hemorrhage
Authors: Stephan A. Mayer, Jennifer A. Frontera, Brian Jankowitz, Christopher P. Kellner, Nathan Kuppermann, Bhiken I. Naik, Daniel K. Nishijima, Thorsten Steiner, Joshua N. Goldstein, Simone Glynn, Andrei Kindzelski, Christopher Loftus, Yvo Roos, Jonathan Rosand, Juliana Tolles, Ronald Warren
Journal: JAMA Network Open (2021)

<h3>Importance</h3> In patients with acute spontaneous or traumatic intracranial hemorrhage, early hemostasis is thought to be critical to minimize ongoing bleeding. However, research evaluating hemostatic therapies has been hampered by a lack of standardized clinical trial outcome measures. <h3>Objective</h3> To identify appropriate primary outcomes for phase 2 and 3 clinical trials of therapies aimed at reducing acute intracranial bleeding. <h3>Evidence Review</h3> A comprehensive review of all previous clinical trials of hemostatic therapy for intracranial bleeding was performed, and studies measuring the frequency, risk factors, and association of intracranial bleeding with outcome of hemorrhage growth were included. <h3>Findings</h3> A hierarchy of 3 outcome measures is recommended, with the first choice being a global patient-centered clinical outcome scale measured 30 to 180 days after the event; the second, a combined clinical and radiographic end point associating hemorrhage expansion with a poor patient-centered outcome at 24 hours or later; and the third, a radiographic measure of hemorrhage expansion at 24 hours alone. Additional recommendations stress the importance of separating various subtypes of bleeding when possible, early treatment within a standardized treatment window, and the routine use of computerized planimetry comparing continuous measures of absolute and relative hemorrhage growth as either a primary or secondary end point. <h3>Conclusions and Relevance</h3> Standardization of outcome measures in studies of intracranial bleeding and hemostatic therapy will support comparative effectiveness research and meta-analysis, with the goal of accelerating the translation of research into clinical practice. The 3 outcome measures proposed in this consensus statement could help this process.
T cell-oriented strategies for controlling the COVID-19 pandemic
Authors: Ji Yun Noh, Hye Won Jeong, Jerome H. Kim, Eui-Cheol Shin
Journal: Nature reviews. Immunology (2021)

COVID-19 vaccination programmes are ongoing worldwide. Neutralizing antibodies are thought to be key for host protection against COVID-19; however, strategies that focus only on neutralizing antibodies may not be sufficient to cope with the pandemic in the longer term owing to the decay of antibody titres and the emergence of antibody-escape variants of SARS-CoV-2. Here, we describe the protective roles of T cells in COVID-19 and the conservation of T cell epitopes in SARS-CoV-2 variants of concern, and discuss the potential contribution of T cell-oriented strategies to controlling the COVID-19 pandemic. This Comment article proposes that T cell-oriented vaccine strategies should be considered to control the COVID-19 pandemic in the longer term, given declining levels of neutralizing antibodies with time after vaccination or infection and the emergence of viral escape variants.
Abstract 11192: Qualitative OCT Assessment in Late Catch-up Lesions After DES Implantations
Authors: Ryo Arikawa, Hiroshi Yamaguchi, Junichiro Takaoka, Akihiro Miyamura, Nobuhiko Atsuchi, Toshiko Ninomiya, Yoshihiko Atsuchi
Journal: Circulation (2012)

Background: The pathophysiology of late catch-up after drug-eluting stent (DES) implantation remains unknown. Methods: To address this issue, we examined patients who underwent follow-up coronary a...
Temporal Trends (1986-1997) in Cholesterol Assessment and Management Practices in Patients Hospitalized with Acute Myocardial Infarction: A Population-Based Perspective
Authors: Jorge L Yarzebski, Frederick A Spencer, Robert J Goldberg, Darleen Lessard, Joel M Gore
Journal: Circulation (2001)

P42 Background: Elevated serum cholesterol levels are associated with increased risk of acute myocardial infarction (AMI) and adverse patient outcomes. It is unclear what proportion of patients have their serum cholesterol measured during hospitalization for AMI and are treated with lipid lowering therapy. The objectives of this longitudinal study were to examine trends over a decade long experience in serum cholesterol ordering practices during hospitalization for AMI and use of lipid lowering therapy. Methods: Observational study of 5204 residents of the Worcester, MA, metropolitan area hospitalized with validated AMI in all greater Worcester hospitals in seven one-year periods between 1986 and 1997. Results: Increases in the measurement of serum cholesterol levels during hospitalization for AMI were observed between 1986 and 1991 after which time there was a progressive decrease; only 24% of AMI patients in 1997 underwent cholesterol testing. Younger age, male sex, and absence of a history of cardiovascular disease were associated with an increased likelihood of serum cholesterol being measured. While the relative use of lipid lowering therapy increased significantly over time (0.4% in 1986; 10.7% in 1997), the absolute rate of utilization of lipid lowering therapy remained low. In patients with an elevated serum cholesterol (&gt;240 mg/dL), 1.9% received lipid lowering therapy in 1986 and 36.6% in 1997. Conclusions: These findings suggest recent declines in the assessment of total cholesterol levels in patients hospitalized with AMI. While the use of lipid lowering therapy during hospitalization for AMI has increased over time, considerable room for improvement remains.
World Trade Center Health Program — United States, 2012−2020
Authors: Alejandro Azofeifa, Gayatri R. Martin, Albeliz Santiago-Colón, Dori B. Reissman, John Howard
Journal: MMWR Surveillance Summaries (2021)

Problem/Condition: After the September 11, 2001, terrorist attacks on the United States, approximately 400,000 persons were exposed to toxic contaminants and other factors that increased their risk for certain physical and mental health conditions.Shortly thereafter, both federal and nonfederal funds were provided to support various postdisaster activities, including medical monitoring and treatment.In 2011, as authorized by the James Zadroga 9/11 Health and Compensation Act of 2010, the CDC World Trade Center (WTC) Health Program began providing medical screening, monitoring, and treatment of 9/11-related health conditions for WTC responders (i.e., persons who were involved in rescue, response, recovery, cleanup, and related support activities after the September 11, 2001, terrorist attacks) and affected WTC survivors (i.e., persons who were present in the dust or dust cloud on 9/11 or who worked, lived, or attended school, child care centers, or adult day care centers in the New York City disaster area).
Scoping review: the empowerment of Alzheimer’s Disease caregivers with mHealth applications
Authors: Eunhee Kim, Andrius Baskys, Anandi V. Law, Moom R. Roosan, Yan Li, Don Roosan
Journal: npj Digital Medicine (2021)

Abstract Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative chronic diseases. As it progresses, patients become increasingly dependent, and their caregivers are burdened with the increasing demand for managing their care. Mobile health (mHealth) technology, such as smartphone applications, can support the need of these caregivers. This paper examines the published academic literature of mHealth applications that support the caregivers of AD patients. Following the PRISMA for scoping reviews, we searched published literature in five electronic databases between January 2014 and January 2021. Twelve articles were included in the final review. Six themes emerged based on the functionalities provided by the reviewed applications for caregivers. They are tracking, task management, monitoring, caregiver mental support, education, and caregiver communication platform. The review revealed that mHealth applications for AD patients’ caregivers are inadequate. There is an opportunity for industry, government, and academia to fill the unmet need of these caregiver.
Endoscopic submucosal dissection of high-grade dysplasia recurrence in ulcerative colitis using a multitraction technique
Authors: Clara Yzet, Thomas Lambin, Pierre Lafeuille, Mathurin Fumery, Joanna Pofelski, Eddy Cotte, Mathieu Pioche
Journal: Endoscopy (2021)

Endoscopic submucosal dissection (ESD) is the gold standard for removing superficial tumor in the digestive tract [1]. Dyplasia in inflammatory bowel disease (IBD) patient is a major concern due to the risk of neoplastic progression. ESD for dysplasia in IBD is feasible, but long-term follow-up data are lacking especially for the management of dysplasia recurrence in an area previously treated by ESD [2] [3] [4] [5].
Moving the Goalposts for Blood Pressure — Time to Act
Authors: Mark R. Nelson
Journal: New England Journal of Medicine (2021)

We often lament the lack of confirmatory studies that can either reassure us all that the previous evidence for a trialed intervention is robust or indicate that the evidence is questionable. Zhang and colleagues have conducted such a study — the STEP trial1 — which in essence investigates the veracity of the findings of the previous trial SPRINT,2 but in an older cohort and in China, a country with a considerable burden of high blood pressure and stroke. The investigators have demonstrated impressive organizational skills in completing recruitment for such a large multicenter trial within a calendar year. As in . . .
Testing Monoclonal Antibodies for Rabies Prophylaxis
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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Rugby players lose cognitive function and blood flow to the brain over one season, study shows
Authors: Luke Taylor
Journal: BMJ (2021)

The brain function and cognitive ability of a team of rugby players declined over the course of a single season, a UK study has found.

A team of professional Rugby Union players were less able to remember, carry out mental tasks, and formulate ideas as the season went on, adding to growing evidence that head collisions in some sports could be making players more susceptible to neurodegenerative diseases in later life.1

The study, published in the Journal of Experimental Physiology , also found that players had reduced blood flow to the brain, particularly those who experienced more collisions. “We’ve provided a sniff of a potential underlying mechanism that could explain accelerated cognitive decline in later life,” said Damian Bailey, the study’s lead author and professor of physiology and biochemistry at the University of South Wales.

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The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine
Authors: Marco Napoli, Avani A. Deshpande, Elsa R. Flores
Journal: Cancer Research (2021)

Abstract In 1990, Baker and colleagues reported their seminal findings in Cancer Research focusing on the transition from adenoma to carcinoma of the colon. By sequencing the TP53 locus in 58 colorectal tumors (25 adenomas and 33 carcinomas) and measuring its allelic deletions, they discovered that this transition requires the loss of one TP53 allele and the mutation of the other one. Here, we discuss how this landmark discovery shed a new light on p53 mutations, prompting the generation of novel mouse models that definitively proved the mutant p53 gain-of-function hypothesis suggested by these results. Finally, we evaluate the implications that the Vogelstein model of cancer progression had on numerous aspects of cancer biology and cancer care, including the characterization of tumor evolution and the response to therapy, and how it ultimately contributed to the wider adoption of early detection screenings and personalized medicine. See related article by Baker and colleagues, Cancer Res 1990;50:7717–22