tbuckley/cabot-search huggingface dataset:
Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy
Authors: Najim Lahrouchi, Alex V. Postma, Christian M. Salazar, Daniel M. De Laughter, Fleur Tjong, Lenka Piherová, Forrest Z. Bowling, Dominic Zimmerman, Elisabeth M. Lodder, Asaf Ta-Shma, Zeev Perles, Leander Beekman, Aho Ilgun, Quinn Gunst, Mariam Hababa, Doris Škorić-Milosavljević, Viktor Stránecký, Viktor Tomek, Peter de Knijff, Rick de Leeuw, Jamille Y. Robinson, Sabrina C. Burn, Hiba Mustafa, Matthew Ambrose, Timothy Moss, Jennifer Jacober, Dmitriy M. Niyazov, Barry Wolf, Katherine H. Kim, Sara Cherny, Andreas Rousounides, Aphrodite Aristidou-Kallika, George Tanteles, Bruel Ange-Line, Anne-Sophie Denommé-Pichon, Christine Francannet, Damara Ortiz, Monique C. Haak, Arend D. J. Ten Harkel, Gwendolyn T.R. Manten, Annemiek C. Dutman, Katelijne Bouman, Monia Magliozzi, Francesca Clementina Radio, Gijs W.E. Santen, Johanna C. Herkert, H. Alex Brown, Orly Elpeleg, Maurice J.B. van den Hoff, Barbara Mulder, Michael V. Airola, Stanislav Kmoch, Joey V. Barnett, Sally-Ann Clur, Michael A. Frohman, Connie R. Bezzina
Journal: Journal of Clinical Investigation (2021)

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
Direct Molecular Evidence for an Ancient, Conserved Developmental Toolkit Controlling Posttranscriptional Gene Regulation in Land Plants
Authors: Haiyan Jia, Kelsey Aadland, Oralia Kolaczkowski, Bryan Kolaczkowski
Journal: Molecular Biology and Evolution (2021)

Abstract In plants, miRNA production is orchestrated by a suite of proteins that control transcription of the pri-miRNA gene, post-transcriptional processing and nuclear export of the mature miRNA. Post-transcriptional processing of miRNAs is controlled by a pair of physically interacting proteins, hyponastic leaves 1 (HYL1) and Dicer-like 1 (DCL1). However, the evolutionary history and structural basis of the HYL1–DCL1 interaction is unknown. Here we use ancestral sequence reconstruction and functional characterization of ancestral HYL1 in vitro and in Arabidopsis thaliana to better understand the origin and evolution of the HYL1–DCL1 interaction and its impact on miRNA production and plant development. We found the ancestral plant HYL1 evolved high affinity for both double-stranded RNA (dsRNA) and its DCL1 partner before the divergence of mosses from seed plants (∼500 Ma), and these high-affinity interactions remained largely conserved throughout plant evolutionary history. Structural modeling and molecular binding experiments suggest that the second of two dsRNA-binding motifs (DSRMs) in HYL1 may interact tightly with the first of two C-terminal DCL1 DSRMs to mediate the HYL1–DCL1 physical interaction necessary for efficient miRNA production. Transgenic expression of the nearly 200 Ma-old ancestral flowering-plant HYL1 in A. thaliana was sufficient to rescue many key aspects of plant development disrupted by HYL1− knockout and restored near-native miRNA production, suggesting that the functional partnership of HYL1–DCL1 originated very early in and was strongly conserved throughout the evolutionary history of terrestrial plants. Overall, our results are consistent with a model in which miRNA-based gene regulation evolved as part of a conserved plant “developmental toolkit.”
Molecular subtype variation within metastasis of urothelial carcinoma.
Authors: Alla Kozubenko, Sonali Arora, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew Caleb Hsieh
Journal: Journal of Clinical Oncology (2021)

471 Background: Molecular subtyping of cancer based on gene expression is a new prognostic tool with potential to guide treatment in the future. Urothelial carcinoma is one such cancer for which numerous molecular subtyping systems have been developed, but the diversity of these systems has hindered their clinical application. Recently, a consensus classification system was derived from six independent systems, defining six molecular classes with distinct oncogenic mechanisms and mutations (Kamoun A, et al. 2020). Considering the high heterogeneity in urothelial carcinoma, we hypothesized that molecular subtype variation may occur between primary and metastatic samples. We further evaluated whether variation in subtype was associated with any unique patient characteristics. Methods: As part of the University of Washington Bladder Cancer Rapid Autopsy Program (BCRAP), primary and metastatic tumor tissue samples were acquired from 14 deceased patients with urothelial carcinoma within 6 hours of death. Patient history was collected and deidentified for analysis. RNA exome sequencing was used for assigning molecular subtype for each of the 61 tumor samples, using the consensus and six comprising systems. Results: Molecular subtype variation within metastatic tumors according to any classification system was detected in 8 out of 14 patients, independent of histologic morphologies. Amongst the patients with variation, on average 2.1 out of 7 classification systems identified a major difference in subtype between sites. Patients with variation (mean age 70 years (SD 7 years)) were older than those without variation (mean age 59 years (SD 11 years), P = 0.04). Furthermore, patients with variation tended to have decreased survival from diagnosis and received less chemotherapy, although these were not statistically significant (p &gt; 0.05). Conclusions: Molecular subtype variation within metastasis is relatively common amongst BCRAP patients with urothelial carcinoma. Older patients are more likely to have variation, possibly due to a higher tumor mutation burden. Potential variation must be taken into account when considering prognosis and developing a recommended drug regimen specific to molecular subtypes.
FAPI Uptake in a Vertebral Body Fracture in a Patient With Lung Cancer
Authors: Junhao Wu, Huipan Liu, Lei Ou, Guohao Jiang, Chunyin Zhang
Journal: Clinical Nuclear Medicine (2021)

A left pulmonary nodule was identified by CT scan in a 53-year-old woman who had a car accident 10 days earlier. 18F-FDG PET/CT showed multiple FDG-avid lesions located at the left lung nodule, mediastinal lymph nodules, and L4 vertebral body. 68Ga-FAPI PET/CT was performed for further evaluation. However, 68Ga-FAPI demonstrated intense FAPI uptake in the accident-related fracture of the L4 vertebral body. This case documents that the fracture of the vertebral body may cause FAPI uptake, and nuclear clinicians evaluating 68Ga-FAPI imaging should be aware of this potential pitfall.
Sterilization and disinfection methods for decellularized matrix materials: Review, consideration and proposal
Authors: Meihan Tao, Tianrang Ao, Xiaoyan Mao, Xinzhu Yan, Rabia Javed, Weijian Hou, Yang Wang, Cong Sun, Shuang Lin, Tianhao Yu, Qiang Ao
Journal: Bioactive Materials (2021)

Sterilization is the process of killing all microorganisms, while disinfection is the process of killing or removing all kinds of pathogenic microorganisms except bacterial spores. Biomaterials involved in cell experiments, animal experiments, and clinical applications need to be in the aseptic state, but their physical and chemical properties as well as biological activities can be affected by sterilization or disinfection. Decellularized matrix (dECM) is the low immunogenicity material obtained by removing cells from tissues, which retains many inherent components in tissues such as proteins and proteoglycans. But there are few studies concerning the effects of sterilization or disinfection on dECM, and the systematic introduction of sterilization or disinfection for dECM is even less. Therefore, this review systematically introduces and analyzes the mechanism, advantages, disadvantages, and applications of various sterilization and disinfection methods, discusses the factors influencing the selection of sterilization and disinfection methods, summarizes the sterilization and disinfection methods for various common dECM, and finally proposes a graphical route for selecting an appropriate sterilization or disinfection method for dECM and a technical route for validating the selected method, so as to provide the reference and basis for choosing more appropriate sterilization or disinfection methods of various dECM.
Geographic variation in systemic therapy in men age 66 years and older with de novo metastatic castration-sensitive prostate cancer: A population-based study in a single payer health-system.
Authors: Christopher J.D. Wallis, Shawn Malone, Ilias Cagiannos, Scott Carlyle Morgan, Robert James Hamilton, Naveen S. Basappa, Cristiano Ferrario, Geoffrey Gotto, Ricardo Fernandes, Tamim Niazi, Krista Noonan, Fred Saad, Sebastien J. Hotte, Huong Hew, Katherine Chan, Laura Park-Wyllie, Bobby Shayegan
Journal: Journal of Clinical Oncology (2021)

50 Background: Significant developments in the standard of care for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) have been reported over the past decade. Treatment intensification with systemic therapies in addition to androgen deprivation therapy (ADT) alone is guideline recommended for most patients. We studied the geographic variation in the use of systemic therapy for de novo mCSPC in Ontario, Canada, a single-payer health system. Methods: We performed a population-based study of men aged 66 years and older diagnosed with de novo mCSPC between 2014-2019. We linked population-based healthcare databases, as administered at the level of Local Health Integration Networks (LHINs) in Ontario, to examine treatment patterns following diagnosis of de novo mCSPC. We categorized initial mCSPC treatments as those begun within 60 days preceding and 6 months following diagnosis and examined the proportion of patients receiving LHRH alone, first generation anti-androgen (AA) alone, combined androgen blockade (CAB; LHRH + 1 st gen AA), ADT + abiraterone acetate + prednisone (AAP), and, ADT + docetaxel (D). In aggregate, we considered LHRH alone, AA alone and CAB as “standard ADT”, and ADT + AAP and ADT + D as “ADT-plus”. Multinomial logistic regression analyses were used to examine the association between receiving systemic treatment intensification (“ADT-plus”) or no prostate cancer pharmacotherapy relative to ADT across geographic regions, while adjusting for baseline patient and disease characteristics. Results: We identified 3,556 men over 66 with de novo mCSPC. Overall, 2794 (78.6%) received standard ADT, 311 (8.7%) did not receive prostate cancer-directed pharmacotherapy, and 451 patients (12.7%) of patients received “ADT-plus”. Utilization of AAP increased from 0.5% to 3% following the LATITUDE data release in 2017, while D decreased from 12% to 10%. There was significant variation in treatment strategies between geographic regions in use of “ADT-plus” ranging from 7 to 20% (p &lt; 0.0001), a difference which persisted after accounting for patient demographics, comorbidity, rurality, and disease characteristics (p = 0.036). Conclusions: Despite proven survival benefits in randomized controlled trials, intensified treatment with docetaxel or abiraterone in addition to ADT was infrequently utilized in this population-based study of men age 66 years and over with mCSPC.
V-V ECMOにて重症肺炎に伴ったARDSを救命し得た一例
Authors: 新名荘史, 溝淵正寛, 青柳慶憲, 上林大輔, 小林智子, 後藤秀樹, 根来伸治, 中村茂, 加藤修
Journal: Circulation (2004)
Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions
Authors: M. Ghezzi, S. Pescina, C. Padula, P. Santi, E. Del Favero, L. Cantù, S. Nicoli
Journal: Journal of Controlled Release (2021)

Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues related to drug administration, from the low water-solubility to the poor drug permeability across biological barriers. With respect to other nanocarriers, polymeric micelles generally display smaller size, easier preparation and sterilization processes, and good solubilization properties, unfortunately associated with a lower stability in biological fluids and a more complicated characterization. Particularly challenging is the study of their interaction with the biological environment, essential to predict the real in vivo behavior after administration. In this review, after a general presentation on micelles features and properties, different characterization techniques are discussed, from the ones used for the determination of micelles basic characteristics (critical micellar concentration, size, surface charge, morphology) to the more complex approaches used to figure out micelles kinetic stability, drug release and behavior in the presence of biological substrates (fluids, cells and tissues). The techniques presented (such as dynamic light scattering, AFM, cryo-TEM, X-ray scattering, FRET, symmetrical flow field-flow fractionation (AF4) and density ultracentrifugation), each one with their own advantages and limitations, can be combined to achieve a deeper comprehension of polymeric micelles in vivo behavior. The set-up and validation of adequate methods for micelles description represent the essential starting point for their development and clinical success.
Abstract 15523: Predictors of ICD Shocks Post Left Ventricular Assist Device Implantation
Authors: Jaimin Trivedi, Henri Roukoz, Adarsh Bhan, Mustafa Ahmed, Geetha Bhat, Ashwin Ravichandran, Jennifer Cowger, Rahul Dhawan, Rajakrishnan Vijayakrishnan, Mark S Slaughter, Rakesh Gopinathannair
Journal: Circulation (2019)

Introduction: Use of continuous flow left ventricular assist devices (CFVAD) have substantially increased. Ventricular arrhythmias are common following VAD implant and can result in ICD shocks. Hyp...
Mohamed Mohamed Eid Soliman
Authors: Faris Soliman
Journal: BMJ (2021)

It is with great sadness that the family of Mohamed Mohamed Eid Soliman announces his passing at the age of 73. He died peacefully at Blackpool Victoria Hospital, surrounded by his family.

Mohamed was born in Egypt the city of El-Mansoura. He was the third of eight siblings, raised in a small family home. Together with his brothers and sisters, he enjoyed a close and loving family upbringing.

After qualifying from El-Mansoura Medical School in 1973, he spent two years working at the university hospital, before moving to Lebanon in 1975. It was here, during the Lebanon civil war, that Mohamed saw the best and the worst of people. He saw the tragedies of war, but …
A hierarchical deep learning approach with transparency and interpretability based on small samples for glaucoma diagnosis
Authors: Yongli Xu, Man Hu, Hanruo Liu, Hao Yang, Huaizhou Wang, Shuai Lu, Tianwei Liang, Xiaoxing Li, Mai Xu, Liu Li, Huiqi Li, Xin Ji, Zhijun Wang, Li Li, Robert N. Weinreb, Ningli Wang
Journal: npj Digital Medicine (2021)

Abstract The application of deep learning algorithms for medical diagnosis in the real world faces challenges with transparency and interpretability. The labeling of large-scale samples leads to costly investment in developing deep learning algorithms. The application of human prior knowledge is an effective way to solve these problems. Previously, we developed a deep learning system for glaucoma diagnosis based on a large number of samples that had high sensitivity and specificity. However, it is a black box and the specific analytic methods cannot be elucidated. Here, we establish a hierarchical deep learning system based on a small number of samples that comprehensively simulates the diagnostic thinking of human experts. This system can extract the anatomical characteristics of the fundus images, including the optic disc, optic cup, and appearance of the retinal nerve fiber layer to realize automatic diagnosis of glaucoma. In addition, this system is transparent and interpretable, and the intermediate process of prediction can be visualized. Applying this system to three validation datasets of fundus images, we demonstrate performance comparable to that of human experts in diagnosing glaucoma. Moreover, it markedly improves the diagnostic accuracy of ophthalmologists. This system may expedite the screening and diagnosis of glaucoma, resulting in improved clinical outcomes.
The BARCODE1 pilot study targeting men with increased genetic risk of developing prostate cancer: Examining the feasibility of a community-based screening program using polygenic risk score to target screening.
Authors: Jana Kathlyn McHugh, Sarah Benafif, Holly ni Raghallaigh, Elizabeth Bancroft, Zsofia Kote-Jarai, Ros A. Eeles
Journal: Journal of Clinical Oncology (2021)

227 Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 1434 men were invited by letter to participate. The uptake was 26%, of whom 87% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 297 men. 25 participants had PRS in the top 10% and were invited for screening; 19 underwent a prostate MRI, and 18 went on to have a systematic (+/- targeted prostate biopsy. There were 7 diagnoses of PrCa (38.9%). The cancers detected were low-risk and are being managed with Active Surveillance (AS). Results of the first year of follow up will be presented and an update of the main study which aims to recruit 5000 men. Conclusions: The BARCODE1 pilot has shown the feasibility of this population-based study, with an overall uptake of 26% and a cancer incidence of nearly 40%. We have identified approximately 70 Primary care providers who have contributed to the transition to the full BARCODE1 study, which will aim to recruit 5,000 men. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: IRAS257684.
Safety and efficacy of nivolumab in older patients (pts) with renal cell carcinoma: Results of a sub-group analysis of the GETUG-AFU 26 NIVOREN multicenter phase II study.
Authors: Loic Mourey, Cécile Dalban, Sylvie Negrier, Christine Chevreau, Gwenaelle Gravis, Constance Thibault, Brigitte Laguerre, Philippe Barthelemy, Delphine Borchiellini, Marine Gross-Goupil, Lionnel Geoffrois, Frederic Rolland, Antoine Thiery-Vuillemin, Florence Joly, Sylvain Ladoire, Florence Tantot, Bernard Escudier, Laurence Albiges
Journal: Journal of Clinical Oncology (2021)

331 Background: NIVOREN GETUG AFU 26 study, is a french multicenter prospective study to evaluate safety and efficacy of Nivolumab (N) in a broad “real world setting” in mRCC after failure of 1 or 2 tyrosine kinase inhibitors. Methods: Between February 2016 and July 2017, 729 pts were enrolled across 27 institutions. Primary objective of the trial was safety assessed by grade ≥ 3 treatment related adverse event (TRAE). We report here results of older patients above 70 years old ([70;75[; [75;80[; ≥ 80) compared with their younger counterparts. Results: Overall, 720 patients were treated (median age 64 (22;90)). Among them 205 pts were ≥ 70 (28.5%) divided as follow: [70-75[:107 (14.9%) / [75-80[: 68 (9,4%) / ≥ 80: 30 (4,2%). Patients’ characteristics (Table) were similar in younger and older patients except for IMDC risk groups (IMDC) classification with less poor prognostic in pts ≥ 75 and fewer brain metastasis in pts ≥ 70. Treatment duration was similar across age groups despite a rate of discontinuation for TRAE increasing with age. Regarding efficacy, there was a non-significant trend toward improved response rate and progression free survival and lower specific survival with increasing age. Conclusions: In this large “real world” setting study a significant number of old pts were included. Prognostic profile appears better in older pts included. There is no signal for an excess of toxicity in this population and efficacy is comparable to younger patients. Age alone should not prevent prescribing N in mRCC. Clinical trial information: NCT03013335 . [Table: see text]
Challenges in the rollout of COVID-19 vaccines worldwide
Authors: Talha Khan Burki
Journal: The Lancet Respiratory Medicine (2021)

On Feb 24, 2021, 600 000 doses of the Oxford–AstraZeneca COVID-19 vaccine arrived in Ghana. 2 days later, 500 000 doses of the same vaccine landed in the Ivory Coast. The west African nations are the first countries to receive the product as part of the COVAX initiative, a joint endeavour between WHO, Gavi, and the Coalition for Epidemic Preparedness Innovations, which aims to ensure that the COVID-19 vaccines are equitably distributed around the world. Demand for the vaccines will far exceed supply this year and there are growing concerns that poorer countries will get left behind.
Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID‐19 patients
Authors: Yasutaka Mitamura, Daniel Schulz, Saskia Oro, Nick Li, Isabel Kolm, Claudia Lang, Reihane Ziadlou, Ge Tan, Bernd Bodenmiller, Peter Steiger, Angelo Marzano, Nicolas de Prost, Olivier Caudin, Mitchell Levesque, Corinne Stoffel, Peter Schmid‐Grendelmeier, Emanual Maverakis, Cezmi A. Akdis, Marie‐Charlotte Brüggen
Journal: Allergy (2021)

Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR.
Judge overturns decision to strike consultant surgeon off medical register
Authors: Clare Dyer
Journal: BMJ (2021)

A High Court judge has quashed a tribunal’s decision to strike a consultant orthopaedic surgeon off the UK medical register, after concluding that the tribunal adopted a “fundamentally erroneous methodology in its approach to the evidence.”1

Muhammad Khan appealed to the High Court after a medical practitioners tribunal decided he should be struck off for behaving in a sexually motivated way towards three colleagues at Barnsley Hospital NHS Foundation Trust. The …