tbuckley/cabot-search huggingface dataset:
Blockchain technology for immunisation documentation in India: findings from a simulation pilot
Authors: Joy C Liu, Sinchan Banerjee, Anshul Bhagi, Aurobindo Sarkar, Bhrigu Kapuria, Shrey Desai, Venkatraman Sethuraman, Sumeet Patil, Somalee Banerjee
Journal: The Lancet Global Health (2021)

BackgroundImmunisation documentation in India has historically been fragmented over a number of systems. To reduce errors and wasted vaccinations for one of the largest and most complex public vaccination systems, data storage has migrated to electronic application-based data records. However, the system remains fragmented. There has been much interest in the global health sector about the use of blockchain technology to build secure, immutable databases for complex data in fragmented environments. As part of the Indian government's innovation initiatives, our project aims to describe a blockchain immunisation system to store immunisation data, pilot its use in India, and assess strengths, limitations, and feasibility of blockchain immunisation.MethodsA connector database—Anveshan—was developed for the state of Gujarat, India, to: (1) remove data fragmentation; (2) enable aggregate analysis to allow tracking of dynamic data; (3) track data changes; and (4) enable fault tolerance so data can be accurately preserved for long periods of time. Although live piloting was not possible because of the COVID-19 pandemic, a simulated pilot was done. A report including lessons learned, benefits and challenges of blockchain application to immunisation documentation, and recommendations for future usage was delivered.FindingsResults from the simulation showed that the Anveshan database was able to decrease data fragmentation by querying across both supply and delivery databases. Aggregate analysis capability was increased through development of a dashboard user interface that allowed policymakers and immunisation programme staff to receive real-time query feedback. Data changes could be tracked and private data encrypted by incorporating disincentives for inappropriate data modification. Blockchain technology properties increased fault tolerance, which make data less corruptible. Although blockchain technology offers benefits for data storage, it does not facilitate improvements in data collection and quality, which remain a significant challenge in India. Multiple health-care stakeholders would need to work together and have access to live data to ensure nationwide scalability.InterpretationOur findings show the challenges and benefits of a private blockchain system and identify areas requiring continued improvement for immunisation documentation in India. One important consideration in infrastructure design on a nationwide scale is the design of the blockchain system itself. This study is an important first step to show that evidence-based design innovation using blockchain can help countries such as India to address complex public health-care delivery conundrums.FundingIndia Grand Challenges grant (Bill & Melinda Gates Foundation and BIRAC, Government of India).
Role of CA 125, CA19-9 and CEA in predicting outcome following neoadjuvant chemotherapy in muscle invasive bladder cancer.
Authors: Hamed Ahmadi, Seyedeh Sanam Ladi Seyedian, Sharath Reddy, Charles Nguyen, Sumeet Bhanvadia, Anne K. Schuckman, Hooman Djaladat, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2021)

496 Background: We have previously shown the prognostic value of three tumor markers (TMs) including Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) in muscle invasive bladder cancer (MIBC). Current report presents an update on TM levels before and after neoadjuvant chemotherapy (NAC) and their association with oncological outcomes. Methods: Serum levels of three TMs were prospectively measured in patients with MIBC who underwent NAC between 2011 and 2019. Rate of pathological upstaging (Path-U) and recurrence-free (RFS) was compared between patients with: (1) Elevated versus normal pre-NAC TM (2) Elevated versus normal post-NAC TM, and (3) Elevated pre-NAC TMs with normalized post-NAC TMs (TM responders) versus persistently elevated post-NAC TMs (TM non responders). Results: Of a total of 199 patients, 63 patients had both pre- and post-NAC TMs. 33/63 (52%) patients had elevated pre-NAC TM of whom, 15/33 (45%) were TM responders. Patients with elevated pre-NAC TM had significantly higher rate of Path-U compared to those with normal pre-NAC TM (62% vs. 22.5%, respectively; P &lt; 0.001). There was no significant difference in Path-U in the other two comparison groups. Patients with elevated pre- and post-NAC TM had significantly lower RFS. Compared to TM responders, TM non responders had significantly higher rate of recurrence (70% vs 34%) and shorter median time to recurrence (4.2 months vs 13.5 months) (P = 0.03). In six patients with recurrence who had complete post cystectomy TM, TM recurrence preceded clinical recurrence by median of 1.2 months (IQR 0.8 – 2.4 months). Conclusions: Elevated TM prior to NAC is associated with pathologic upstaging. TM elevation pre- or post-NAC predicts a worse outcome. Post-cystectomy TM might play a role in earlier detection of recurrence.
SARS-CoV-2 Seroprevalence and Symptom Onset in Culturally Linked Orthodox Jewish Communities Across Multiple Regions in the United States
Authors: Israel Zyskind, Avi Z. Rosenberg, Jason Zimmerman, Hiam Naiditch, Aaron E. Glatt, Abraham Pinter, Elitza S. Theel, Michael J. Joyner, D. Ashley Hill, Miriam R. Lieberman, Elliot Bigajer, Daniel Stok, Elliot Frank, Jonathan I. Silverberg
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the United States are still emerging. <h3>Objective</h3> To elucidate SARS-CoV-2 seroprevalence and symptom onset in a culturally linked community across 5 states in the United States. <h3>Design, Setting, and Participants</h3> This cross-sectional study included adults (aged ≥18 years) recruited from the orthodox Jewish community across 5 states (California, Connecticut, Michigan, New Jersey, and New York) in 3 geographically distinct areas of the United States between May 13 and July 6, 2020. Participants completed an online survey and underwent SARS-CoV-2 antibody testing. <h3>Main Outcomes and Measures</h3> Seroprevalence and date of symptom onset of SARS-CoV-2. <h3>Results</h3> Overall, 9507 adults (mean [SD] age, 39.6 [15.0] years; 3777 [39.7%] women) completed the SARS-CoV-2 survey, of whom 6665 (70.1%) had immunoglobin G anti–SARS-CoV-2 antibody levels assessed. A high seroprevalence of SARS-CoV-2 antibodies was observed across all communities, with the highest proportion of positive testing observed in New Jersey (1080 of 3323 [32.5%]) and New York (671 of 2196 [30.6%]). Most individuals with a positive SARS-CoV-2 immunoglobin G antibody test reported a date of symptom-onset between March 9 and March 31, 2020 (California: 135 of 154 [87.7%]; Connecticut: 32 of 34 [94.1%]; Michigan: 44 of 50 [88.0%]; New Jersey: 964 of 1168 [82.5%]; New York: 571 of 677 [84.3%]). This start date was coincident with the Jewish festival of Purim, celebrated March 9 to 10, 2020, with extensive intracommunity spread in the weeks following (mean and mode of peak symptom onset, March 20, 2020), occurring in the absence of strong general and culture-specific public health directives. <h3>Conclusions and Relevance</h3> This cross-sectional study of orthodox Jewish adults across the US found that socioculturally bound communities experienced early parallel outbreaks in discrete locations, notably prior to substantive medical and governmental directives. Further research should clarify optimal national, local, community-based, and government policies to prevent outbreaks in social and cultural communities that traditionally gather for holidays, assemblies, and festivals.
Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD): A phase II trial (ANZUP1601).
Authors: Craig Gedye, Abhishek Jagdish Joshi, Alison Yan Zhang, Andrew James Martin, Anthony M. Joshua, Carole A. Harris, Craig Underhill, David William Pook, Guy C. Toner, Ganessan Kichenadasse, Jane Yeojeong So, Jeffrey C. Goh, Michelle Frances Morris, Nicola Jane Lawrence, Tom Ferguson, Paul Austin Vasey, Prashanth Prithviraj, Shalini Subramaniam, Martin R. Stockler, Ian D. Davis
Journal: Journal of Clinical Oncology (2021)

TPS367 Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A sample size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .
Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens
Authors: Efthymia Papalexi, Eleni P. Mimitou, Andrew W. Butler, Samantha Foster, Bernadette Bracken, William M. Mauck, Hans-Hermann Wessels, Yuhan Hao, Bertrand Z. Yeung, Peter Smibert, Rahul Satija
Journal: Nature Genetics (2021)
Factors associated with perceived stress in patients with vitiligo in the ComPaRe e-cohort
Authors: Morgane Condamina, Jason Shourick, Julien Seneschal, Emilie Sbidian, Nicolas Andreu, Isabelle Pane, Philippe Ravaud, Viet-Thi Tran, Khaled Ezzedine
Journal: Journal of the American Academy of Dermatology (2021)
Engineered Microglia Potentiate the Action of Drugs against Glioma Through Extracellular Vesicles and Tunneling Nanotubes
Authors: Yitian Du, Zhenzhen Yang, Qi Sun, Meng Lin, Rudong Wang, Yiwei Peng, Xinyi Chen, Xianrong Qi
Journal: Advanced Healthcare Materials (2021)

Gliomas remain difficult to treat because of their metastatic and recurrent nature and the existence of the blood-brain barrier (BBB), which impedes drug delivery. Microglia, the resident macrophages in the CNS, can be recruited by gliomas and can penetrate the tumor. In this study, microglia (BV2 cells) are used as transport vectors to deliver paclitaxel for the treatment of glioma. To avoid paclitaxel toxicity in microglia, liposomes are first employed to isolate the drug from BV2 cells. Dipalmitoyl phosphatidylserine (DPPS), as an "eat me" signal, is doped into liposomes to amplify their phagocytosis by microglia. This study demonstrates that engineered microglia can cross the BBB, independently migrate toward gliomas, and transfer cargo to glioma cells. Of note, extracellular vesicles and tunneling nanotubes are found to offer unique modes of cargo transportation between microglia and glioma cells. In vivo, the engineered drug-loaded microglia has a high ability to target the brain, penetrate glioma, and suppress tumor progression, supporting the notion that the use of engineered microglia is a potential strategy for the treatment of glioma. These findings present new opportunities for exploration into the use of microglia as transport vectors to deliver therapeutic agents through specific membrane nanotubes and vesicles.
A Global eDelphi Exercise to Identify Core Domains and Domain Items for the Development of a Global Registry of Alopecia Areata Disease Severity and Treatment Safety (GRASS)
Authors: Dmitri Wall, Nekma Meah, Katherine York, Bevin Bhoyrul, Laita Bokhari, Leonardo Spagnol Abraham, Roisín Adams, Wilma Bergfeld, Regina C. Betz, Ulrike Blume-Peytavi, Valerie Callender, Chel Campbell, Jen Chambers, Gang Chen, Vijaya Chitreddy, George Cotsarelis, Brittany Craiglow, Rachita Dhurat, Ncoza Dlova, Jeff Donovan, Bruna Duque-Estrada, Samantha Eisman, Abby Ellison, Paul Farrant, Juan Ferrando Barberá, Aida Gadzhigoroeva, Ramon Grimalt, Matthew Harries, Maria Hordinsky, Alan D. Irvine, Victoria Jolliffe, Leslie Jones, Brett King, Won-Soo Lee, Nino Lortkipanidze, Amy McMichael, Andrew Messenger, Paradi Mirmirani, Elise Olsen, Seth J. Orlow, Yuliya Ovcharenko, Bianca Maria Piraccini, Rodrigo Pirmez, Adriana Rakowska, Pascal Reygagne, Melissa Riley, Lidia Rudnicka, David Saceda Corralo, Jerry Shapiro, Pooja Sharma, Tatiana Silyuk, Spartak Kaiumov, Desmond J. Tobin, Antonella Tosti, Sergio Vañó-Galván, Annika Vogt, Martin Wade, Leona Yip, Abraham Zlotogorski, Cheng Zhou, Rodney Sinclair
Journal: JAMA Dermatology (2021)

A recent expert consensus exercise emphasized the importance of developing a global network of patient registries for alopecia areata to redress the paucity of comparable, real-world data regarding the effectiveness and safety of existing and emerging therapies for alopecia areata.To generate core domains and domain items for a global network of alopecia areata patient registries.Sixty-six participants, representing physicians, patient organizations, scientists, the pharmaceutical industry, and pharmacoeconomic experts, participated in a 3-round eDelphi process, culminating in a face-to-face meeting at the World Congress of Dermatology, Milan, Italy, June 14, 2019.Ninety-two core data items, across 25 domains, achieved consensus agreement. Twenty further noncore items were retained to facilitate data harmonization in centers that wish to record them. Broad representation across multiple stakeholder groups was sought; however, the opinion of physicians was overrepresented.This study identifies the domains and domain items required to develop a global network of alopecia areata registries. These domains will facilitate a standardized approach that will enable the recording of a comprehensive, comparable data set required to oversee the introduction of new therapies and harness real-world evidence from existing therapies at a time when the alopecia areata treatment paradigm is being radically and positively disrupted. Reuse of similar, existing frameworks in atopic dermatitis, produced by the Treatment of Atopic Eczema (TREAT) Registry Taskforce, increases the potential to reuse existing resources, creates opportunities for comparison of data across dermatology subspecialty disease areas, and supports the concept of data harmonization.
Abstract 14983: CMV Mismatch in Heart Transplantation: The Inadequacy of Antibiotic Prophylaxis and PSI in the Current Era
Authors: Evan Kransdorf, Rachel Zabner, Jignesh Patel, Michele Hamilton, David H Chang, Lawrence Czer, Fardad Esmailian, Sadia J Dimbil, Ryan Levine, Jon A Kobashigawa
Journal: Circulation (2019)

Introduction: CMV mismatch (donor positive, recipient negative CMV serology) has been observed to increase the development of CMV infection (defined as clinically symptomatic with detected viremia)...
Pulmonary long-term consequences of COVID-19 infections after hospital discharge
Authors: Jose-Ramon Blanco, Maria-Jesus Cobos-Ceballos, Francisco Navarro, Isabel Sanjoaquin, Francisco Arnaiz de las Revillas, Enrique Bernal, Luis Buzon-Martin, Miguel Viribay, Lourdes Romero, Simona Espejo-Perez, Borja Valencia, David Ibañez, Diego Ferrer-Pargada, Damian Malia, Fernando-Gustavo Gutierrez-Herrero, Julian Olalla, Bernabe Jurado-Gamez, Javier Ugedo
Journal: Clinical Microbiology and Infection (2021)
Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses
Authors: Fan Huang, Christophe Gonçalves, Margarita Bartish, Joelle Rémy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galán, Tomasz Rzymski, Milena Mazan, Magdalena Masiejczyk, Jacek Faber, Elie Khoury, Alexandre Benoit, Natascha Gagnon, David Dankort, Fabrice Journe, Ghanem E. Ghanem, Connie M. Krawczyk, H. Uri Saragovi, Ciriaco A. Piccirillo, Nahum Sonenberg, Ivan Topisirovic, Christopher E. Rudd, Wilson H. Miller, Sonia V. del Rincón
Journal: Journal of Clinical Investigation (2021)

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and myeloid-derived suppressor cells, and increased CD8+ T cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like TCF1+PD-1+CD8+ T cells, a characteristic essential for durable antitumor immunity, was detected in mice given a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy.
Feasibility of Deep Learning-Guided Attenuation and Scatter Correction of Whole-Body 68Ga-PSMA PET Studies in the Image Domain
Authors: Samaneh Mostafapour, Faeze Gholamiankhah, Habibollah Dadgar, Hossein Arabi, Habib Zaidi
Journal: Clinical Nuclear Medicine (2021)

Objective This study evaluates the feasibility of direct scatter and attenuation correction of whole-body 68 Ga-PSMA PET images in the image domain using deep learning. Methods Whole-body 68 Ga-PSMA PET images of 399 subjects were used to train a residual deep learning model, taking PET non–attenuation-corrected images (PET-nonAC) as input and CT-based attenuation-corrected PET images (PET-CTAC) as target (reference). Forty-six whole-body 68 Ga-PSMA PET images were used as an independent validation dataset. For validation, synthetic deep learning–based attenuation-corrected PET images were assessed considering the corresponding PET-CTAC images as reference. The evaluation metrics included the mean absolute error (MAE) of the SUV, peak signal-to-noise ratio, and structural similarity index (SSIM) in the whole body, as well as in different regions of the body, namely, head and neck, chest, and abdomen and pelvis. Results The deep learning–guided direct attenuation and scatter correction produced images of comparable visual quality to PET-CTAC images. It achieved an MAE, relative error (RE%), SSIM, and peak signal-to-noise ratio of 0.91 ± 0.29 (SUV), −2.46% ± 10.10%, 0.973 ± 0.034, and 48.171 ± 2.964, respectively, within whole-body images of the independent external validation dataset. The largest RE% was observed in the head and neck region (−5.62% ± 11.73%), although this region exhibited the highest value of SSIM metric (0.982 ± 0.024). The MAE (SUV) and RE% within the different regions of the body were less than 2.0% and 6%, respectively, indicating acceptable performance of the deep learning model. Conclusions This work demonstrated the feasibility of direct attenuation and scatter correction of whole-body 68 Ga-PSMA PET images in the image domain using deep learning with clinically tolerable errors. The technique has the potential of performing attenuation correction on stand-alone PET or PET/MRI systems.
Endothelial Pannexin 1 Regulates Cardiac Response to Myocardial Infarction
Authors: Miranda E. Good, Alexander P. Young, Abigail G. Wolpe, Manxiu Ma, Philip J. Hall, Colleen K. Duffy, Mark J. Aronovitz, Gregory L. Martin, Robert M. Blanton, Norbert Leitinger, Scott R. Johnstone, Matthew J. Wolf, Brant E. Isakson
Journal: Circulation Research (2021)
The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.
Authors: Justin Shaya, Aaron Lee, Angelo Cabal, Justine Panian, James Michael Randall, Frederick E. Millard, Tyler Francis Stewart, Brent S. Rose, John Kellogg Parsons, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]