tbuckley/cabot-search huggingface dataset:
NLRP3 Inflammasome Mediates Immune-Stromal Interactions in Vasculitis
Authors: Rebecca A. Porritt, David Zemmour, Masanori Abe, Youngho Lee, Meena Narayanan, Thacyana T. Carvalho, Angela C. Gomez, Daisy Martinon, Chintda Santiskulvong, Michael C. Fishbein, Shuang Chen, Timothy R. Crother, Kenichi Shimada, Moshe Arditi, Magali Noval Rivas
Journal: Circulation Research (2021)

Rationale: NLRP3 (NLR family pyrin domain containing 3) activation and IL-1β (interleukin-1β) production are implicated in Kawasaki disease (KD) pathogenesis; however, a detailed and complete characterization of the molecular networks and cellular subsets involved in the development of cardiovascular lesions is still lacking. Objective: Here, in a murine model of KD vasculitis, we used single-cell RNA sequencing and spatial transcriptomics to determine the cellular landscape of inflamed vascular tissues. Methods and Results: We observe infiltrations of innate and adaptive immune cells in murine KD cardiovascular lesions, associated with increased expression of Nlrp3 and Il1b . Monocytes, macrophages, and dendritic cells were the main sources of IL-1β, whereas fibroblasts and vascular smooth muscle cells (VSMCs) expressed high levels of IL-1 receptor. VSMCs type 1 surrounding the inflamed coronary artery undergo a phenotype switch to become VSMCs type 2, which are characterized by gene expression changes associated with decreased contraction and enhanced migration and proliferation. Genetic inhibition of IL-1β signaling on VSMCs efficiently attenuated the VSMCs type 2 phenotypic switch and the development of cardiovascular lesions during murine KD vasculitis. In addition, pharmacological inhibition of NLRP3 prevented the development of cardiovascular inflammation. Conclusions: Our studies unravel the cellular diversity involved in IL-1β production and signaling in murine KD cardiovascular lesions and provide the rationale for therapeutic strategies targeting NLRP3 to inhibit cardiovascular lesions associated with KD.
The acute surgical unit: An updated systematic review and meta-analysis
Authors: Ned Kinnear, Samantha Jolly, Matheesha Herath, Jennie Han, Minh Tran, Michael O’Callaghan, Derek Hennessey, Christopher Dobbins, Tarik Sammour, James Moore
Journal: International Journal of Surgery (2021)

To systematically review comparative studies on the acute surgical unit (ASU) model.Searches were performed of Cochrane, Embase, Medline and grey literature. Eligible articles were comparative studies of the Acute Surgical Unit (ASU) model published 01/01/2000-12/03/2020. Amongst patients with any diagnosis, primary outcomes were length of stay, after-hours operating, complications and cost. Secondary outcomes were time to surgical review, time to theatre, mortality and re-admission for patients with any diagnosis, and cholecystectomy during index admission for patients with biliary disease. Additional analyses were planned for specific cohorts, such as patients with appendicitis or cholecystitis.Searches returned 9,677 results from which 77 eligible publications were identified, representing 150,981 unique patients. Cohorts were adequately homogenous for meta-analysis of all outcomes except cost. For patients with any diagnosis, compared with the Traditional model, the introduction of an ASU model was associated with reduced length of stay (mean difference [MD] 0.68 days; 95% confidence interval [CI] 0.38-0.98), after-hours operating rates (odds ratio [OR] 0.56; 95% CI 0.46-0.69) and complications (OR 0.48, 95% CI 0.33-0.70). Regarding cost, two studies reported savings following ASU introduction, while one found no difference. Amongst secondary outcomes, for patients with any diagnosis, ASU commencement was associated with reduced time to surgical review, time to theatre and mortality. Re-admissions were unchanged. For patients with biliary disease, ASU establishment was associated with superior rates of index cholecystectomy.Compared to the Traditional structure, the ASU model is superior for most metrics. ASU introduction should be promoted in policy for widespread benefit.
Thank you to our peer reviewers in 2020
Authors: Laura Hart
Journal: The Lancet Neurology (2021)

In 2020, the COVID-19 pandemic severely impacted neurological services and their patients, and the resulting heightened burden was felt by neurologists.1 A year later, that impact is still being felt by many of our readers worldwide. Despite the undoubtedly difficult personal and professional pressures, our reviewers have continued to provide their constructive expert advice, enabling The Lancet Neurology to publish content that advocates change in and illuminates neurological clinical practice.
Letter by Allard-Ratick et al Regarding Article, “Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women”
Authors: Marc P. Allard-Ratick, Cian P. McCarthy, Ik-Kyung Jang
Journal: Circulation (2021)
ACC/AHA Statement on Cost/Value Methodology in Clinical Practice Guidelines and Performance Measures
Authors: Jeffrey L. Anderson, Paul A. Heidenreich, Paul G. Barnett, Mark A. Creager, Gregg C. Fonarow, Raymond J. Gibbons, Jonathan L. Halperin, Mark A. Hlatky, Alice K. Jacobs, Daniel B. Mark, Frederick A. Masoudi, Eric D. Peterson, Leslee J. Shaw
Journal: Journal of the American College of Cardiology (2014)
Improvement in time to oral anticancer agent follow-up.
Authors: Emily Johengen, Arielle Davidson, Kathleen W. Beekman, Kelly Hecht, Emily R. Mackler
Journal: Journal of Clinical Oncology (2021)

235 Background: Use of oral anticancer agents (OAAs) for cancer treatment continues to grow and creates a need for oncology practices to adapt their ambulatory infusion model of care to one that supports patients taking anti-cancer treatment at home. Historically, our practice has had success with care managers supporting infusion treatment patients. A recently published randomized trial has shown considerable benefits of dedicated pharmacist follow-up for patients taking OAAs. As a result, our practice added a dedicated oncology pharmacist to provide education and follow-up for our OAA patients. Methods: This is a single-center, retrospective evaluation of time to first follow up for patients taking OAAs pre-intervention (11/1/20 - 2/28/21) versus post-intervention (3/1/21 - 4/30/21). The intervention consists of structured symptom and adherence monitoring by a dedicated oncology pharmacist as part of our care management team for all patients prescribed an OAA. In the pre-intervention group, OAA monitoring was divided between care team members without a dedicated OAA program. The population consists of 139 patients newly started on OAAs over the 6-month period. “On-time” follow up defined by our practice is follow up that is &lt;10 days from the OAA start date. There were 20 patients (10 per group) excluded from data analysis due to being deceased before follow-up could be assessed (n= 3), transferring oncology care elsewhere (n= 5), or never starting the OAA (n= 12). Results: Pre-intervention, initial follow up occurred via pharmacist or nurse care manager visit (n=47), provider visit (n=29), or unplanned admission (n=3). Post-intervention, all but two initial follow up visits were performed by the designated oncology pharmacist, and there were no unplanned admissions prior to first follow up. The median time to first follow up visit was 8 days (range 2 to 31 days) in the pre-intervention group (n=79) and 7 days (range 3 to 15 days) in the post-intervention group (n=40). Follow up visits occurred within 10 days of OAA initiation for 67.1% of patients in the pre-intervention group and 95% of patients in the post-intervention group (p=&lt;0.001). Follow up occurred within 14 days of initiation for 82.3% of pre-intervention patients and 97.5% of post-intervention patients (p=0.018). Conclusions: Post-intervention assessment showed improvement in the time to follow up for patients taking OAAs. Future analyses will include outcomes, such as interventions at the time of follow-up, length on therapy, and unplanned admissions.
Targeting KRAS: Good, But Is It Good Enough?
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2021)

Targeting KRAS: Good, But Is It Good Enough?R ecently, the FDA granted accelerated approval to sotorasib, a drug targeting a specific KRAS mutation (G12C) in non-small cell lung cancer.The approval was based on a study by Skoulidis et al, 1 published in late June in The New England Journal of Medicine.This was a single-arm phase II trial involving 126 patients whose tumors carried this specific mutation, which occurs in about 13% of KRAS-driven lung cancers.In these patients, the response rate was 37.1%, median progression-free survival was 6.8 months, and median overall survival was 12.5 months.During the short follow-up period, the median duration of response was 11.1 months.Why was this a big deal?For years, I have worked beside brilliant scientists who studied cancer signaling pathways, and it was generally held that targeting KRAS was the "holy grail."In fact, the NCI put millions into establishing the "RAS Initiative" for the primary purpose of promoting the successful development of these drugs.KRAS had been considered "undruggable," but after the structure was studied from every possible angle, a weak link was identified and the race to come up with a drug began.The G12C mutation is just the beginning; theoretically, every possible mutation can eventually be targeted.I expected this drug and others like it to be blockbusters, to "knock it out of the park," and to turn KRAS-driven cancers into mere shadows of their former selves.I expected this to work similar to how imatinib beat down chronic myelogenous leukemia.I knew better than to think every tumor would respondpreclinical studies showed that not all cell lines died out when you shut down the KRAS pathway-but I really did think that we would see transformative and durable benefit in more patients.Please don't get me wrong.The benefit seen with sotorasib is real and it's important.I have no issue with the accelerated approval, especially given the favorable safety profile; but I honestly expected more.Responses occurred less frequently than observed with tyrosine kinase inhibitors approved for other driver mutations in lung cancer.I didn't expect that.Clearly, we need to know more.Would the results have been different in a patient population that had received much less previous therapy?Do the resistance mechanisms have an antidote?Are there other pathways that must also be suppressed when you target KRAS?The possibilities, of course, are endless, and I have no doubt that our thoracic oncology colleagues will sort this out over time.I am also puzzled why this drug doesn't seem to work as well in other diseases in which KRAS mutations occur, like colorectal cancer.In an earlier phase I trial, the response rate was only 7.1%. 2 This is another knowledge gap to fill.Despite all these concerns, though, I consider this a watershed moment in the history of cancer therapy.Another victory for our patients!And I know more will come.
Use of PARP Inhibitors for Ovarian Cancer
Authors: Deborah K. Armstrong
Journal: Journal of the National Comprehensive Cancer Network (2021)

PARP inhibitors have been used to treat numerous diseases, but these agents have been approved the longest for use in ovarian cancer. All trials of PARP inhibitor maintenance in newly diagnosed ovarian cancer are positive for prolonged progression-free survival (PFS), but patients with BRCA mutations consistently derive the most benefit. Testing for homologous recombination deficiency may provide information regarding the degree of PFS benefit. In individuals without a BRCA mutation, PARP inhibition also prolongs PFS after chemotherapy for platinum-sensitive, PARP-naïve disease. As in the up-front setting, patients with BRCA mutations derive the most benefit in these trials. Finally, PARP inhibitors are active as monotherapy in PARP-naïve, BRCA -mutated relapsed disease, with increased activity observed in platinum-sensitive versus platinum-resistant disease.
Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed
Authors: J Peter Figueroa, Peter J. Hotez, Carolina Batista, Yanis Ben Amor, Onder Ergonul, Sarah Gilbert, Mayda Gursel, Mazen Hassanain, Gagandeep Kang, David C. Kaslow, Jerome H. Kim, Bhavna Lall, Heidi Larson, Denise Naniche, Timothy Sheahan, Shmuel Shoham, Annelies Wilder-Smith, Samba O. Sow, Nathalie Strub-Wourgaft, Prashant Yadav, Maria Elena Bottazzi
Journal: PLoS Medicine (2021)

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.
Enhancing Cognitive Restructuring with Concurrent Repetitive Transcranial Magnetic Stimulation: A Transdiagnostic Randomized Controlled Trial
Authors: Andrada D. Neacsiu, Lysianne Beynel, John P. Powers, Steven T. Szabo, Lawrence G. Appelbaum, Sarah H. Lisanby, Kevin S. LaBar
Journal: Psychotherapy and Psychosomatics (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Emotional dysregulation constitutes a serious public health problem in need of novel transdiagnostic treatments. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To this aim, we developed and tested a one-time intervention that integrates behavioral skills training with concurrent repetitive transcranial magnetic stimulation (rTMS). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Forty-six adults who met criteria for at least one DSM-5 disorder and self-reported low use of cognitive restructuring (CR) were enrolled in a randomized, double-blind, sham-controlled trial that used a between-subjects design. Participants were taught CR and underwent active rTMS applied at 10 Hz over the right (&lt;i&gt;n&lt;/i&gt; = 17) or left (&lt;i&gt;n&lt;/i&gt; = 14) dorsolateral prefrontal cortex (dlPFC) or sham rTMS (&lt;i&gt;n&lt;/i&gt; = 15) while practicing reframing and emotional distancing in response to autobiographical stressors. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Those who received active left or active right as opposed to sham rTMS exhibited enhanced regulation (&lt;i&gt;d&lt;/i&gt;s = 0.21–0.62) as measured by psychophysiological indices during the intervention (higher high-frequency heart rate variability, lower regulation duration). Those who received active rTMS over the left dlPFC also self-reported reduced distress throughout the intervention (&lt;i&gt;d&lt;/i&gt; = 0.30), higher likelihood to use CR, and lower daily distress during the week following the intervention. The procedures were acceptable and feasible with few side effects. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; These findings show that engaging frontal circuits simultaneously with cognitive skills training and rTMS may be clinically feasible, well-tolerated and may show promise for the treatment of transdiagnostic emotional dysregulation. Larger follow-up studies are needed to confirm the efficacy of this novel therapeutic approach.
Transcatheter Compared With Surgical Aortic Valve Replacement in Patients With Previous Chest-Directed Radiation Therapy
Authors: Farhang Yazdchi, Sameer A Hirji, Anju Nohria, Edward Percy, Morgan Harloff, Alexandra Malarczyk, Paige Newell, Mariam B Kerolos, Siobhan McGurk, Prem Shekar, Pinak Shah, Tsuyoshi Kaneko
Journal: JACC CardioOncology (2021)

Cardiac surgery for radiation-induced valvular disease is associated with adverse outcomes. Transcatheter aortic valve replacement (TAVR) is increasingly used in patients with a history of chest-directed radiation therapy and aortic stenosis (CRT-AS).We examined outcomes of TAVR compared with surgical aortic valve replacement (SAVR) for patients with CRT-AS.We identified 69 patients with CRT-AS who underwent TAVR from January 2012 to September 2018. Operative mortality, postoperative morbidities, and length of hospitalization were compared with 117 contemporaneous patients with CRT-AS who underwent isolated SAVR. Age-adjusted survival was evaluated by means of Cox proportional hazards modeling.Compared with SAVR patients, TAVR patients were older (mean age 75 ± 11.5 vs 65 ± 11.5 years), with more comorbidities, such as chronic obstructive pulmonary disease, atrial fibrillation, and peripheral vascular disease (all P < 0.050). Operative mortality was 4.3% for SAVR vs 1.4% for TAVR (P = 0.41). Most SAVR deaths (4 of 5) occurred in the intermediate-/high-risk group (Society for Thoracic Surgeons predicted risk of operative mortality >3%; P = 0.026). The ratio of observed to expected mortality was better for low-risk SAVR patients and all TAVR patients (0.72 [95% confidence interval [CI]: 0.59-0.86] and 0.24 [95% CI: 0.05-0.51], respectively) compared with intermediate-/high-risk SAVR patients (2.52 [95% CI: 0.26-4.13]). SAVR patients had significantly longer median intensive care unit and overall length of stay and higher blood transfusion requirements but similar rates of stroke and pacemaker implantation.TAVR was associated with excellent in-hospital outcomes and better survival compared with intermediate-/high-risk SAVR in patients with CRT-AS. While SAVR still has a role in low-risk patients or those for whom TAVR is unsuitable for technical or anatomical reasons, TAVR is emerging as the standard of care for intermediate-/high-risk CRT-AS patients.
Long COVID: to investigate immunological mechanisms and sex/gender related aspects as fundamental steps for tailored therapy
Authors: Elena Ortona, Walter Malorni
Journal: European Respiratory Journal (2021)

<b>Long COVID was detected in both adults and children and is characterised by immunological dysregulation. Autoimmune reactions in adult patients and allergic reactions in children appear to be critical factors.</b>https://bit.ly/38RfSyT
Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin‐rich thrombus
Authors: Ellen G. Driever, Fien A. von Meijenfeldt, Jelle Adelmeijer, Robbert J. de Haas, Marius C. van den Heuvel, Chandrasekaran Nagasami, John W. Weisel, Constantino Fondevila, Robert J. Porte, Anabel Blasi, Nigel Heaton, Stephen Gregory, Pauline Kane, William Bernal, Yoh Zen, Ton Lisman
Journal: Hepatology (2021)

Abstract Background and Aim Portal vein thrombosis (PVT) is a common complication of cirrhosis. The exact pathophysiology remains largely unknown, and treatment with anticoagulants does not lead to recanalization of the portal vein in all patients. A better insight into the structure and composition of portal vein thrombi may assist in developing strategies for the prevention and treatment of PVT. Approach and Results Sixteen prospectively and 63 retrospectively collected nonmalignant portal vein thrombi from patients with cirrhosis who underwent liver transplantation were included. Histology, immunohistochemistry, and scanning electron microscopy were used to assess structure and composition of the thrombi. Most recent CT scans were reanalyzed for thrombus characteristics. Clinical characteristics were related to histological and radiological findings. All samples showed a thickened, fibrotic tunica intima. Fibrin‐rich thrombi were present on top of the fibrotic intima in 9/16 prospective cases and in 21/63 retrospective cases. A minority of the fibrotic areas stained focally positive for fibrin/fibrinogen (16% of cases), von Willebrand factor (VWF; 10%), and CD61 (platelets, 21%), while most of the fibrin‐rich areas stained positive for those markers (fibrin/fibrinogen, 100%; VWF, 77%; CD61, 100%). No associations were found between clinical characteristics including estimated thrombus age and use of anticoagulants and presence of fibrin‐rich thrombi. Conclusion We demonstrate that PVT in patients with cirrhosis consists of intimal fibrosis with an additional fibrin‐rich thrombus in only one‐third of cases. We hypothesize that our observations may explain why not all portal vein thrombi in patients with cirrhosis recanalize by anticoagulant therapy.
Implementation of a mortality risk predictive analytics model.
Authors: Stephanie Broadnax Broussard, John Russell Hoverman, Lalan S. Wilfong, Sabrina Q. Mikan, Holly Books, Lance Ortega, Terry Lynn Jensen, Sara Toth, Duc Vo
Journal: Journal of Clinical Oncology (2021)

211 Background: Improving the quality of End of Life (EOL) care continues to be a challenge. Enhanced prognostic awareness is critical for all members of the clinical team. In December 2020, The McKesson Advance Care Planning Enrollment eXtended (APEX) mortality risk predictive analytics model was implemented to improve prognostic awareness in OCM population and improve the timing of initiation of end of life care. (See ASCO 2021 abstract #1560). Methods: The APEX tool was provided in collaboration with the McKesson/US Oncology network analytics team. A process was established for dissemination of the report information. In the pilot, 12 practice locations with varying community landscapes, socio-cultural dynamics, and site clinical personnel resources were selected. At each site clinical leads and physician champions were selected. Education was provided on the tool, prognostic variables, and appropriate interventions. Biweekly, each site was provided a list of stratified patients based on their risk of mortality within the next 90 days. Patients that were identified as “very high” or “high” risk were reviewed by the clinical teams and discussed in routine huddles. Physicians and teams reported their planned interventions before and after mortality risk identification. Results: In the pilot, 105 patients were identified as very high or high risk. Reported interventions included the option to continue treatment, ACP Discussion, hospice referral/enrollment, palliative care referral, or continue close monitoring. Prior to the report, 14 identified patients were admitted to hospice and 30 patients had 1 or more advance directives documented. For 26 patients, treatment changes occurred including hospice enrollment, reduction in chemotherapy dosage, change in regimen, or initiating intensive monitoring. 23 patients indicated on the report expired in the interim between generation of the report and receipt by the clinic. No changes in treatment were made in 22 patients. There was physician reported disagreement with the mortality risk assessment in 4 patients. Conclusions: We describe implementation of a mortality predictive model in our practice. The care teams found the tool useful to identify patients at high risk of mortality. Interventions were varied and we will track the outcomes based on intervention. We are using the information from the pilot to continue refining the tool and implementation.