Publications by authors named "David Huang"

911 Publications

PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling.

Genome Med 2021 Apr 14;13(1):58. Epub 2021 Apr 14.

The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China.

Background: Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood.

Methods: In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression.

Results: We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-Apc CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC.

Conclusion: PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.
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http://dx.doi.org/10.1186/s13073-021-00871-5DOI Listing
April 2021

Intact TP53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.

Blood 2021 Apr 6. Epub 2021 Apr 6.

Monash University, Australia.

Selective targeting of BCL2 with the BH3-mimetic venetoclax is proving transformative for patients with various leukemias. TP53 controls apoptosis upstream from where BCL2 and its pro-survival relatives, such as MCL1, act. Therefore, targeting these pro-survival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL2 has produced clinically relevant responses in blood cancers with aberrant TP53. However, we show that TP53 mutated or deficient myeloid and lymphoid leukemias outcompete isogenic controls with intact TP53, unless sufficient concentrations of BH3-mimetics targeting BCL2 or MCL1 are applied. Strikingly, tumor cells with TP53 dysfunction escape and thrive over time if inhibition of BCL2 or MCL1 is sub-lethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study reveals the key role of TP53 in shaping long-term responses to BH3-mimetic drugs and reconciles the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). In contrast to BH3-mimetics targeting just BCL2 or MCL1 at doses which are individually sub-lethal, we find that a combined BH3-mimetic approach targeting both pro-survival proteins enhances lethality and durably suppresses leukemic burden, regardless of TP53 mutation status. Our findings highlight the importance of employing sufficiently lethal treatment strategies to maximize outcomes for patients with TP53-mutant disease. In addition, our findings caution against use of sub-lethal BH3-mimetic drug regimens, which may enhance the risk of disease progression driven by emergent TP53 mutant clones.
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http://dx.doi.org/10.1182/blood.2020010167DOI Listing
April 2021

Hospitalization for Heart Failure and Subsequent Ventricular Tachyarrhythmias in Patients With Left Ventricular Dysfunction.

JACC Clin Electrophysiol 2021 Mar 25. Epub 2021 Mar 25.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, Rochester, New York, USA. Electronic address:

Objectives: This study aimed to evaluate the risk of sustained life-threatening ventricular tachyarrhythmias (VTAs) after hospitalization for heart failure (HHF).

Background: HHF is common among patients with an implantable cardioverter-defibrillator (ICD).

Methods: We analyzed all 5,511 ICD patients enrolled in the landmark MADIT and RAID trials. Multivariate Cox regression was used to evaluate the association of in-trial HHF occurrence with the risk of subsequent VTA and the composite end point of VTA or cardiac death.

Results: Mean age was 64 ± 11 years, 23% were women, 62% were ischemic, and 40% had cardiac resynchronization therapy with defibrillators. The 3-year cumulative rate of VTA subsequent to HHF was significantly higher than the corresponding rate without HHF (44% vs. 24%, respectively; p < 0.001). After multivariable adjustment, time-dependent HHF was shown to be associated with a 79% increased risk for VTA and a 2.9-fold increased risk for VTA/cardiac death (p < 0.001 for both). In-trial development of atrial tachyarrhythmia (ATA) was also identified as an independent risk factor for the VTA and VTA/cardiac death end points (hazard ratios [HRs]: 1.59 and 1.43, respectively; p ≤ 0.001 for both) but did not affect the association of HHF with VTA. Subgroup analysis demonstrated that the association of HHF with the risk of subsequent VTA was maintained among risk subsets categorized by age, sex, history of ATA, and implantation indication, but was significantly more pronounced among patients with nonischemic versus ischemic cardiomyopathy (HRs: 2.54 and 1.43, respectively; p value for interaction: 0.017).

Conclusions: HHF is a powerful risk factor for subsequent VTA in patients implanted with an ICD. These data may be used for improved risk stratification in this population.
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http://dx.doi.org/10.1016/j.jacep.2021.01.021DOI Listing
March 2021

Global Impact of COVID-19 on Stroke Care and Intravenous Thrombolysis.

Authors:
Raul G Nogueira Muhammed M Qureshi Mohamad Abdalkader Sheila Ouriques Martins Hiroshi Yamagami Zhongming Qiu Ossama Yassin Mansour Anvitha Sathya Anna Czlonkowska Georgios Tsivgoulis Diana Aguiar de Sousa Jelle Demeestere Robert Mikulik Peter Vanacker James E Siegler Janika Kõrv Jose Biller Conrad W Liang Navdeep S Sangha Alicia M Zha Alexandra L Czap Christine Anne Holmstedt Tanya N Turan George Ntaios Konark Malhotra Ashis Tayal Aaron Loochtan Annamarei Ranta Eva A Mistry Anne W Alexandrov David Y Huang Shadi Yaghi Eytan Raz Sunil A Sheth Mahmoud H Mohammaden Michael Frankel Eric Guemekane Bila Lamou Hany M Aref Ahmed Elbassiouny Farouk Hassan Tarek Menecie Wessam Mustafa Hossam M Shokri Tamer Roushdy Fred S Sarfo Tolulope Oyetunde Alabi Babawale Arabambi Ernest O Nwazor Taofiki Ajao Sunmonu Kolawole Wahab Joseph Yaria Haytham Hussein Mohammed Philip B Adebayo Anis D Riahi Samia Ben Sassi Lenon Gwaunza Gift Wilson Ngwende David Sahakyan Aminur Rahman Zhibing Ai Fanghui Bai Zhenhui Duan Yonggang Hao Wenguo Huang Guangwen Li Wei Li Ganzhe Liu Jun Luo Xianjin Shang Yi Sui Ling Tian Hongbin Wen Bo Wu Yuying Yan Zhengzhou Yuan Hao Zhang Jun Zhang Wenlong Zhao Wenjie Zi Thomas W Leung Chandril Chugh Vikram Huded Bindu Menon Jeyaraj Durai Pandian P N Sylaja Fritz Sumantri Usman Mehdi Farhoudi Elyar Sadeghi Hokmabadi Anat Horev Anna Reznik Rotem Sivan Hoffmann Nobuyuki Ohara Nobuyuki Sakai Daisuke Watanabe Ryoo Yamamoto Ryosuke Doijiri Naoki Tokuda Takehiro Yamada Tadashi Terasaki Yukako Yazawa Takeshi Uwatoko Tomohisa Dembo Hisao Shimizu Yuri Sugiura Fumio Miyashita Hiroki Fukuda Kosuke Miyake Junsuke Shimbo Yusuke Sugimura Yoshiki Yagita Yohei Takenobu Yuji Matsumaru Satoshi Yamada Ryuhei Kono Takuya Kanamaru Hidekazu Yamazaki Manabu Sakaguchi Kenichi Todo Nobuaki Yamamoto Kazutaka Sonoda Tomoko Yoshida Hiroyuki Hashimoto Ichiro Nakahara Aida Kondybayeva Kamila Faizullina Saltanat Kamenova Murat Zhanuzakov Jang-Hyun Baek Yangha Hwang Jin Soo Lee Si Baek Lee Jusun Moon Hyungjong Park Jung Hwa Seo Kwon-Duk Seo Sung Il Sohn Chang Jun Young Rechdi Ahdab Wan Asyraf Wan Zaidi Zariah Abdul Aziz Hamidon Bin Basri Law Wan Chung Aznita Binti Ibrahim Khairul Azmi Ibrahim Irene Looi Wee Yong Tan Nafisah Wan Yahya Stanislav Groppa Pavel Leahu Amal M Al Hashmi Yahia Zakaria Imam Naveed Akhtar Maria Carissa Pineda-Franks Christian Oliver Co Dmitriy Kandyba Adel Alhazzani Hosam Al-Jehani Carol Huilian Tham Marlie Jane Mamauag Narayanaswamy Venketasubramanian Chih-Hao Chen Sung-Chun Tang Anchalee Churojana Esref Akil Ozlem Aykaç Atilla Ozcan Ozdemir Semih Giray Syed Irteza Hussain Seby John Huynh Le Vu Anh Duc Tran Huy Hoang Nguyen Thong Nhu Pham Thang Huy Nguyen Trung Quoc Nguyen Thomas Gattringer Christian Enzinger Monika Killer-Oberpfalzer Flavio Bellante Sofie De Blauwe Geert Vanhooren Sylvie De Raedt Anne Dusart Robin Lemmens Noemie Ligot Matthieu Pierre Rutgers Laetitia Yperzeele Filip Alexiev Teodora Sakelarova Marina Roje Bedeković Hrvoje Budincevic Igor 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Sedghi Timo Siepmann Kristina Szabo Götz Thomalla Lina Palaiodimou Dimitrios Sagris Odysseas Kargiotis Peter Klivenyi Laszlo Szapary Gabor Tarkanyi Alessandro Adami Fabio Bandini Paolo Calabresi Giovanni Frisullo Leonardo Renieri Davide Sangalli Anne V Pirson Maarten Uyttenboogaart Ido van den Wijngaard Espen Saxhaug Kristoffersen Waldemar Brola Małgorzata Fudala Ewa Horoch-Lyszczarek Michal Karlinski Radoslaw Kazmierski Pawel Kram Marcin Rogoziewicz Rafal Kaczorowski Piotr Luchowski Halina Sienkiewicz-Jarosz Piotr Sobolewski Waldemar Fryze Anna Wisniewska Malgorzata Wiszniewska Patricia Ferreira Paulo Ferreira Luisa Fonseca João Pedro Marto Teresa Pinho E Melo Ana Paiva Nunes Miguel Rodrigues Vítor Tedim Cruz Cristian Falup-Pecurariu Georgi Krastev Miroslav Mako María Alonso de Leciñana Juan F Arenillas Oscar Ayo-Martin Antonio Cruz Culebras Exuperio Diez Tejedor Joan Montaner Soledad Pérez-Sánchez Miguel Angel Tola Arribas Alejandro Rodriguez Vasquez Michael Mazya Gianmarco Bernava 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Neurology 2021 Mar 25. Epub 2021 Mar 25.

Radiation Oncology, Boston Medical Center.

Objective: The objectives of this study were to measure the global impact of the pandemic on the volumes for intravenous thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with two control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases.

Results: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95%CI, -11.7 to - 11.3, p<0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95%CI, -13.8 to -12.7, p<0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95%CI, -13.7 to -10.3, p=0.001). Recovery of stroke hospitalization volume (9.5%, 95%CI 9.2-9.8, p<0.0001) was noted over the two later (May, June) versus the two earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722/52,026) of all stroke admissions.

Conclusions: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.
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http://dx.doi.org/10.1212/WNL.0000000000011885DOI Listing
March 2021

Artificial intelligence in OCT angiography.

Prog Retin Eye Res 2021 Mar 22:100965. Epub 2021 Mar 22.

Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97239, USA; Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA. Electronic address:

Optical coherence tomographic angiography (OCTA) is a non-invasive imaging modality that provides three-dimensional, information-rich vascular images. With numerous studies demonstrating unique capabilities in biomarker quantification, diagnosis, and monitoring, OCTA technology has seen rapid adoption in research and clinical settings. The value of OCTA imaging is significantly enhanced by image analysis tools that provide rapid and accurate quantification of vascular features and pathology. Today, the most powerful image analysis methods are based on artificial intelligence (AI). While AI encompasses a large variety of techniques, machine-learning-based, and especially deep-learning-based, image analysis provides accurate measurements in a variety of contexts, including different diseases and regions of the eye. Here, we discuss the principles of both OCTA and AI that make their combination capable of answering new questions. We also review contemporary applications of AI in OCTA, which include accurate detection of pathologies such as choroidal neovascularization, precise quantification of retinal perfusion, and reliable disease diagnosis.
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http://dx.doi.org/10.1016/j.preteyeres.2021.100965DOI Listing
March 2021

The challenges of generalizability in artificial intelligence for ADME/Tox endpoint and activity prediction.

Expert Opin Drug Discov 2021 Mar 19:1-12. Epub 2021 Mar 19.

Computational Chemistry, Director of Computational Sciences, Computational Chemistry, Takeda Pharmaceuticals, San Diego, USA.

Introduction: Artificial intelligence (AI) has seen a massive resurgence in recent years with wide successes in computer vision, natural language processing, and games. The similar creation of robust and accurate AI models for ADME/Tox endpoint and activity prediction would be revolutionary to drug discovery pipelines. There have been numerous demonstrations of successful applications, but a key challenge remains: how generalizable are these predictive models?

Areas Covered: The authors present a summary of current promising components of AI models in the context of early drug discovery where ADME/Tox endpoint and activity prediction is the main driver of the iterative drug design process. Following that is a review of applicability domains and dataset construction considerations which determine generalizability bottlenecks for AI deployment. Further reviewed is the role of promising learning frameworks - multitask, transfer, and meta learning - which leverage auxiliary data to overcome issues of generalizability.

Expert Opinion: The authors conclude that the most promising direction toward integrating reliable and informative AI models into the drug discovery pipeline is a conjunction of learned feature representations, deep learning, and novel learning frameworks. Such a solution would address the sparse and incomplete datasets that are available for key endpoints related to drug discovery.
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http://dx.doi.org/10.1080/17460441.2021.1901685DOI Listing
March 2021

Predictors of adequate physical activity within a multiethnic polycystic ovary syndrome patient population: a cross-sectional assessment.

BMC Womens Health 2021 Mar 17;21(1):108. Epub 2021 Mar 17.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.

Background: Physical activity is a cornerstone for treatment of women with polycystic ovary syndrome (PCOS), but there are limited data on their exercise behaviors. A previous study identified PCOS patients of non-White ethnicity to be at higher risk for inadequate physical activity. Further data is needed to identify groups that would benefit from additional counseling in achieving adequate physical activity (APA). Therefore, this study examined correlates of APA within a multiethnic PCOS patient population.

Methods: Cross-sectional assessment of exercise behaviors within a multiethnic PCOS patient population was performed using the International Physical Activity Questionnaire (IPAQ). Kruskal-Wallis test was used to compare metabolic equivalents from physical activity among racial/ethnic groups. APA was defined as at least 150 min of moderate-intensity, or 75 min of vigorous-intensity, or an equivalent combination of moderate- and vigorous-intensity activity per week. Logistic regression analyses were performed to identify correlates of APA.

Results: Four hundred and sixty-five women of various racial/ethnic backgrounds were included in analysis: 62% (n = 287) self-identified as White, 15% (n = 71) as Hispanic, 11% (n = 52) as East/Southeast Asian, 7% (n = 32) as South Asian, and 5% (n = 23) as Black/African American. Significant differences were observed in metabolic equivalents (METs) from vigorous-intensity and total (moderate plus vigorous-intensity) exercise across racial/ethnic groups (p < 0.01); South Asian patients had the lowest metabolic expenditure in moderate-intensity, vigorous-intensity, and total exercise. Overall prevalence of APA was 66%; South Asian patients exhibited the lowest prevalence (46.9%). Ethnicity was a predictor for APA when controlled for age (p = 0.01); this finding was attenuated in logistic regression models that also controlled for age and body mass index (p = 0.05) as well as education level and parity (p = 0.16).

Conclusions: South Asian patients with PCOS exhibited the lowest metabolic expenditure and frequency of APA in our cohort. Differences in frequency of APA across racial/ethnic groups appear to be influenced by anthropometric and sociodemographic factors. Our findings present an opportunity for women's health providers to be cognizant and provide additional counseling regarding physical exercise to at-risk PCOS patients to improve their known higher risk for adverse long-term metabolic outcomes.
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http://dx.doi.org/10.1186/s12905-021-01257-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972197PMC
March 2021

Impact of the Coronavirus Disease of 2019 Pandemic on Radiation Oncology Clinical Decision Making in a High-Prevalence Environment.

Adv Radiat Oncol 2021 May-Jun;6(3):100680. Epub 2021 Mar 4.

Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.

Purpose: This study aimed to define how the coronavirus disease of 2019 (COVID-19) pandemic affected the role, timing, and delivery of radiation therapy (RT) in a high-prevalence region at the height of the initial U.S. outbreak.

Methods And Materials: We performed a retrospective review of all patients seen at 3 radiation oncology departments within the Rutgers Robert Wood Johnson Barnabas Health system in New Jersey during the initial COVID-19 surge. The primary endpoints were to define and quantify COVID-related, radiation-specific care changes, and identify predictive factors of experiencing COVID-related care changes.

Results: A total of 545 patients with cancer were seen during the study period, 99 of whom (18.1%) experienced ≥1 COVID-related care change. RT delays were the most common, accounting for 51.5% of all care changes. Physician-directed delays accounted for 41.2% of RT delays, and patient fears, COVID testing, and access barriers were responsible for 27.5%, 17.6%, and 13.7%, respectively. Patient age ( = .040), intent of treatment ( = .047), and cancer type ( < .001) were significantly associated with experiencing a COVID-related care change, as we found that older, curative intent and patients with rectal cancer were more likely to experience care changes. On multivariate analysis, patient age remained significant when controlling for treatment intent and cancer type.

Conclusions: Our study provides a perspective on how care was adapted to protect patients with cancer during a pandemic while maximizing disease control. The positive correlation between age and likelihood of care changes may reflect extra precaution taken with older patients given their vulnerability to severe COVID illness. The lower observed likelihood of COVID-related care changes among patients undergoing palliative RT may reflect either the more urgent needs addressed by palliative RT or simply be logistical, because palliative radiation is often delivered in short courses with less exposure risk. Assessing adaptations others have implemented and monitoring how they affect patient outcomes will be crucial.
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http://dx.doi.org/10.1016/j.adro.2021.100680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929864PMC
March 2021

In vitro activity of iclaprim and comparator agents against Listeria monocytogenes clinical isolates from 2012 to 2018.

J Glob Antimicrob Resist 2021 Mar 1;25:14-17. Epub 2021 Mar 1.

JMI Laboratories, North Liberty, Iowa, USA.

Objectives: This study examined the in vitro activity of iclaprim and comparators against 40 Listeria monocytogenes clinical isolates mostly (95%) from patients with bloodstream infection (BSI) from the USA, Australia/New Zealand, Latin America and Europe collected between 2012-2018.

Methods: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria.

Results: The iclaprim MIC value for all L. monocytogenes was 0.015 μg/mL. The MIC values for iclaprim were 4-fold lower than trimethoprim, the only FDA-approved dihydrofolate reductase inhibitor, against all L. monocytogenes.

Conclusion: Iclaprim demonstrated lower MIC values than trimethoprim against a collection (2012-2018) of L. monocytogenes clinical isolates mostly from patients with BSI from the USA, Australia/New Zealand, Latin America and Europe.
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http://dx.doi.org/10.1016/j.jgar.2021.02.015DOI Listing
March 2021

Artifacts and artifact removal in optical coherence tomographic angiography.

Quant Imaging Med Surg 2021 Mar;11(3):1120-1133

Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.

Optical coherence tomographic angiography (OCTA) enables rapid imaging of retinal vasculature in three dimensions. While the technique has provided quantification of healthy vessels as well as pathology in several diseases, it is not unusual for OCTA data to contain artifacts that may influence measurement outcomes or defy image interpretation. In this review, we discuss the sources of several OCTA artifacts-including projection, motion, and signal reduction-as well as strategies for their removal. Artifact compensation can improve the accuracy of OCTA measurements, and the most effective use of the technology will incorporate hardware and software that can perform such correction.
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http://dx.doi.org/10.21037/qims-20-730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829161PMC
March 2021

Feasibility of Embedding a Scalable, Virtually Enabled Biorepository in the Electronic Health Record for Precision Medicine.

JAMA Netw Open 2021 02 1;4(2):e2037739. Epub 2021 Feb 1.

The Clinical Research, Investigation, and Systems Modeling of Acute illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Importance: A cornerstone of precision medicine is the identification and use of biomarkers that help subtype patients for targeted treatment. Such an approach requires the development and subsequent interrogation of large-scale biobanks linked to well-annotated clinical data. Traditional means of creating these data-linked biobanks are costly and lengthy, especially in acute conditions that require time-sensitive clinical data and biospecimens.

Objectives: To develop a virtually enabled biorepository and electronic health record (EHR)-embedded, scalable cohort for precision medicine (VESPRE) and compare the feasibility, enrollment, and costs of VESPRE with those of a traditional study design in acute care.

Design, Setting, And Participants: In a prospective cohort study, the EHR-embedded screening alert was generated for 3428 patients, and 2199 patients (64%) were eligible and screened. Of these, 1027 patients (30%) were enrolled. VESPRE was developed for regulatory compliance, feasibility, internal validity, and cost in a prospective cohort of 1027 patients (aged ≥18 years) with sepsis-3 within 6 hours of presentation to the emergency department. The VESPRE infrastructure included (1) automated EHR screening, (2) remnant blood collection for creation of a virtually enabled biorepository, and (3) automated clinical data abstraction. The study was conducted at an academic institution in southwestern Pennsylvania from October 17, 2017, to June 6, 2019.

Main Outcomes And Measures: Regulatory compliance, enrollment, internal validity of automated screening, biorepository acquisition, and costs.

Results: Of the 1027 patients enrolled in the study, 549 were included in the proof-of-concept analysis (305 [56%] men); median (SD) age was 59 (17) years. VESPRE collected 12 963 remnant blood and urine samples and demonstrated adequate feasibility for clinical, biomarker, and microbiome analyses. Over the 20-month test, the total cost beyond the existing operations infrastructure was $39 417.50 ($14 880.00 project management, $22 717.50 laboratory supplies/staff, and $1820.00 data management)-approximately $39 per enrolled patient vs $239 per patient for a traditional cohort study.

Conclusions And Relevance: Results of this study suggest that, in a large US health system that collects data using a common EHR platform and centralized laboratory system, VESPRE, a large-scale, inexpensive EHR-embedded infrastructure for precision medicine can be used. Tested in the sepsis setting, VESPRE appeared to capture a high proportion of eligible patients at low incremental cost.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.37739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900864PMC
February 2021

Dehydrogenative Pd and Ni Catalysis for Total Synthesis.

Acc Chem Res 2021 Mar 16;54(5):1118-1130. Epub 2021 Feb 16.

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States.

ConspectusThe development of novel synthetic methods remains a cornerstone in simplifying complex molecule synthesis. Progress in the field of transition metal catalysis has enabled new mechanistic strategies to achieve difficult chemical transformations, increased the value of abundant chemical building blocks, and pushed the boundaries of creative and strategic route design to improve step economy in multistep synthesis. Methodologies to introduce an olefin into saturated molecules continue to be essential transformations because of the plethora of reactions available for alkene functionalization. Of particular importance are dehydrogenation reactions adjacent to electron-withdrawing groups such as carbonyls, which advantageously provide activated olefins that can be regioselectively manipulated. Palladium catalysis occupies a central role in the most widely adopted carbonyl dehydrogenation reactions, but limits to the scope of these protocols persist.In this Account, we describe our group's contributions to the area of transition-metal-catalyzed dehydrogenation using palladium catalysis and more sustainable and economical nickel catalysis. These metals are used in conjunction with allyl and aryl halides or pseudohalides that serve as oxidants to access a unique mechanistic approach for one-step α,β-dehydrogenation of various electron-withdrawing groups, including ketones, esters, nitriles, amides, carboxylic acids, and electron-deficient heteroarenes. The pivotal reaction parameters that can be modified to influence reaction efficiency are highlighted, including base and oxidant structure as well as ligand and salt additive effects. This discussion is expected to serve as a guide for troubleshooting challenging dehydrogenation reactions and provide insight for future reaction development in this area.In addition to enabling dehydrogenation reactions, our group's allyl-Pd and -Ni chemistry can be used for C-C and C-X bond-forming reactions, providing novel disconnections with practical applications for expediting multistep synthesis. These transformations include a telescoped process for ketone α,β-vicinal difunctionalization; an oxidative enone β-functionalization, including β-stannylation, β-silylation, and β-alkylation; and an oxidative cycloalkenylation between unstabilized ketone enolates and unactivated alkenes. These bond-forming methodologies broaden the range of transformations accessible from abundant ketone, enone, and alkene moieties. Both the dehydrogenation and C-C and C-X bond-forming methodologies have been implemented in our group's total synthesis campaigns to provide step-efficient synthetic routes toward diverse natural products.Through the lens of multistep synthesis, the utility and robustness of our dehydrogenation and dehydrogenative functionalization methodologies can be better appreciated, and we hope that this Account will inspire practitioners to apply our methodologies to their own synthetic challenges.
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http://dx.doi.org/10.1021/acs.accounts.0c00787DOI Listing
March 2021

Phylogenomics reveals viral sources, transmission, and potential superinfection in early-stage COVID-19 patients in Ontario, Canada.

Sci Rep 2021 02 12;11(1):3697. Epub 2021 Feb 12.

Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.

The emergence and rapid global spread of SARS-CoV-2 demonstrates the importance of infectious disease surveillance, particularly during the early stages. Viral genomes can provide key insights into transmission chains and pathogenicity. Nasopharyngeal swabs were obtained from thirty-two of the first SARS-CoV-2 positive cases (March 18-30) in Kingston Ontario, Canada. Viral genomes were sequenced using Ion Torrent (n = 24) and MinION (n = 27) sequencing platforms. SARS-CoV-2 genomes carried forty-six polymorphic sites including two missense and three synonymous variants in the spike protein gene. The D614G point mutation was the predominate viral strain in our cohort (92.6%). A heterozygous variant (C9994A) was detected by both sequencing platforms but filtered by the ARTIC network bioinformatic pipeline suggesting that heterozygous variants may be underreported in the SARS-CoV-2 literature. Phylogenetic analysis with 87,738 genomes in the GISAID database identified global origins and transmission events including multiple, international introductions as well as community spread. Reported travel history validated viral introduction and transmission inferred by phylogenetic analysis. Molecular epidemiology and evolutionary phylogenetics may complement contact tracing and help reconstruct transmission chains of emerging diseases. Earlier detection and screening in this way could improve the effectiveness of regional public health interventions to limit future pandemics.
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http://dx.doi.org/10.1038/s41598-021-83355-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881023PMC
February 2021

Outcomes of end-stage renal disease patients in the PROCESS trial.

J Am Coll Emerg Physicians Open 2021 Feb 18;2(1):e12358. Epub 2021 Jan 18.

Department of Emergency Medicine McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth) Houston Texas USA.

Objective: Intravenous fluid administration is a main component of sepsis therapy, but physicians are cautious about giving fluids to end-stage renal disease (ESRD) patients out of concern for causing volume overload. We compared the outcomes of septic shock patients with and without ESRD and evaluated the association between early intravenous fluid administration and outcomes.

Methods: We analyzed patients enrolled in the Protocolized Care for Early Septic Shock (PROCESS) trial, which studied different resuscitation strategies for early septic shock. Stratifying for ESRD, we compared patient characteristics, course of care, and outcomes between ESRD and non-ESRD. Using multivariable logistic regression, we determined the association between 6-hour total fluid volume (> = 30 mL/kg vs < 30 mL/kg) from preenrollment and outcomes.

Results: There were 84 ESRD and 1257 non-ESRD patients. ESRD patients had a higher median Charlson Comorbidity score (5 vs 2,  < .001), higher median acute physiology and chronic health evaluation (APACHE) II score (26.5 vs 20.0,  < .001), and lower 6-hour intravenous fluid administration (54.7 vs 68.3 mL/kg,  < .001). Ninety-day mortality (33.3% vs 29.3%,  = .43) and intubation rate (31.0% vs 33.4%,  = .64) did not differ between groups. Fewer ESRD received > = 30 mL/kg (66.6% vs 86.7%  < .001). For ESRD, receipt of > = 30 mL/kg intravenous fluid did not alter any outcome. For non-ESRD patients, receiving   ≥30 mL/kg of intravenous fluid was associated with increased 90-day mortality (adjusted odds ratio = 1.64; 95% confidence interval, 1.03-2.61).

Conclusions: In the PROCESS trial, ESRD patients had similar outcomes to non-ESRD patients. Although ESRD patients received less intravenous fluid administration, most received over 30 mL/kg in the first 6 hours. In contrast to non-ESRD patients, receiving  ≥30 mL/kg of intravenous fluid was not associated with worse outcomes in ESRD.
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http://dx.doi.org/10.1002/emp2.12358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813517PMC
February 2021

Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.

J Med Chem 2021 01 14;64(2):1139-1169. Epub 2021 Jan 14.

Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (, ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting growth in culture. In addition, we report the first X-ray crystal structures of Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01777DOI Listing
January 2021

Cardiac Resynchronization Therapy and Ventricular Tachyarrhythmia Burden.

Heart Rhythm 2021 Jan 11. Epub 2021 Jan 11.

Clinical Cardiovascular Research Center, University of Rochester, Rochester, New York.

Background: Cardiac resynchronization therapy-defibrillator (CRT-D) may reduce the incidence of first ventricular tachyarrhythmia (VTA) in patients with heart failure (HF) and left bundle branch block (LBBB).

Objective: The purpose of this study was to assess the effect of CRT-D on VTA burden in LBBB patients.

Methods: We included 1281 patients with LBBB from MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). VTA was defined as any treated or monitored sustained ventricular tachycardia (VT ≥180 bpm) or ventricular fibrillation (VF). Life-threatening VTA was defined as VT ≥200 bpm or VF. VTA recurrence was assessed using the Andersen-Gill model.

Results: During a mean follow-up of 2.5 years, 964 VTA episodes occurred in 264 patients (21%). The VTA rate per 100 person-years was significantly lower in the CRT-D group compared with the implantable cardioverter-defibrillator (ICD) group (20 vs. 34; P <0.01). Multivariate analysis demonstrated that CRT-D treatment was associated with a 32% risk reduction for VTA recurrence (hazard ratio 0.68; 95% confidence interval 0.57-0.82; P <0.001), 57% risk reduction for recurrent life-threatening VTA, 54% risk reduction for recurrent appropriate ICD shocks, and 25% risk reduction for the combined endpoint of VTA and death. The effect of CRT-D on VTA burden was consistent among all tested subgroups but was more pronounced among patients in New York Heart Association functional class I. Landmark analysis showed that at 2 years, the cumulative probability of death subsequent to year one was highest (16%) among patients who had ≥2 VTA events during their first year.

Conclusion: In patients with LBBB and HF, early intervention with CRT-D reduces mortality, VTA burden, and frequency of multiple appropriate ICD shocks. VTA burden is a powerful predictor of subsequent mortality.
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http://dx.doi.org/10.1016/j.hrthm.2020.12.034DOI Listing
January 2021

Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

Eur Heart J 2021 Jan 8. Epub 2021 Jan 8.

Division of Cardiology, Department of Medicine, Clinical Cardiovascular Research Center, University of Rochester Medical Center, 265 Crittenden Blvd CU 420653, NY 14642, USA.

Aims: The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks.

Methods And Results: The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability.

Conclusions: We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.
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http://dx.doi.org/10.1093/eurheartj/ehaa1057DOI Listing
January 2021

Eye motion correction algorithm for OCT-based corneal topography.

Biomed Opt Express 2020 Dec 1;11(12):7343-7356. Epub 2020 Dec 1.

The Center for Ophthalmic Optics and Lasers, Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University, Portland, Oregon 97239, USA.

With its sequential image acquisition, OCT-based corneal topography is often susceptible to measurement errors due to eye motion. We have developed a novel algorithm to detect eye motion and minimize its impact on OCT topography maps. We applied the eye motion correction algorithm to corneal topographic scans acquired using a 70 kHz spectral-domain OCT device. OCT corneal topographic measurements were compared to those from a rotating Scheimpflug camera topographer. The motion correction algorithm provided a 2-4 fold improvement in the repeatability of OCT topography and its agreement with the standard Scheimpflug topographer. The repeatability of OCT Zernike-based corneal mean power, cardinal astigmatism, and oblique astigmatism after motion detection was 0.14 D, 0.28 D, and 0.24 D, respectively. The average differences between the two devices were 0.19 D for simulated keratometry-based corneal mean power, 0.23 D for cardinal astigmatism, and 0.25 D for oblique astigmatism. Our eye motion detection method can be applied to any OCT device, and it therefore represents a powerful tool for improving OCT topography.
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http://dx.doi.org/10.1364/BOE.412209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747916PMC
December 2020

The activity of the diaminopyrimidine dihydrofolate reducatase inhibitor, iclaprim, against Toxoplasma gondii in an in vitro model: a pilot study.

Authors:
David B Huang

Diagn Microbiol Infect Dis 2021 Apr 24;99(4):115296. Epub 2020 Dec 24.

Motif BioSciences, New York, NY, USA; Rutgers New Jersey Medical School, Newark, NJ, USA. Electronic address:

The objective of this pilot study was to examine the activity of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, in an in vitro infection model of infection with Toxoplasma gondii. Toxoplasma growth was assessed by enzyme linked immunoassay (ELISA) performed directly on the fixed cultures using a peroxidase labeled monoclonal antibody directed against the SAG-l surface protein of T. gondii. For each well, the results were expressed as optical density (OD) values. Iclaprim inhibited T. gondii growth at concentrations between 0.1 and 10 mg/L; the IC was estimated at 0.26 mg/L (95% confidence interval 0.22-0.33). Iclaprim was about 10 times more active than trimethoprim, which had an IC of 2.3 mg/L. Iclaprim demonstrated synergistic effects at concentrations of 0.02, 0.05 and 0.1 mg/L when combined with subinhibitory concentrations of sulfamethoxazole (0.1 or 0.02 mg/L). These results show that iclaprim is a potent inhibitor of T. gondii growth in vitro. In addition, iclaprim exhibited synergy in vitro when tested in the presence of sulfamethoxazole. Iclaprim should be further investigated as an agent for the treatment or prophylaxis of toxoplasmosis.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115296DOI Listing
April 2021

Mechanistic insights into the synergistic activation of the RXR-PXR heterodimer by endocrine disruptor mixtures.

Proc Natl Acad Sci U S A 2021 01;118(1)

Centre de Biologie Structurale, INSERM, CNRS, Université de Montpellier, Montpellier, France;

Humans are chronically exposed to mixtures of xenobiotics referred to as endocrine-disrupting chemicals (EDCs). A vast body of literature links exposure to these chemicals with increased incidences of reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, chemicals have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects. Our previous work shed light on a mechanism by which a binary mixture of xenobiotics activates PXR in a synergistic fashion. Structural analysis revealed that mutual stabilization of the compounds within the ligand-binding pocket of PXR accounts for the enhancement of their binding affinity. In order to identify and characterize additional active mixtures, we combined a set of cell-based, biophysical, structural, and in vivo approaches. Our study reveals features that confirm the binding promiscuity of this receptor and its ability to accommodate bipartite ligands. We reveal previously unidentified binding mechanisms involving dynamic structural transitions and covalent coupling and report four binary mixtures eliciting graded synergistic activities. Last, we demonstrate that the robust activity obtained with two synergizing PXR ligands can be enhanced further in the presence of RXR environmental ligands. Our study reveals insights as to how low-dose EDC mixtures may alter physiology through interaction with RXR-PXR and potentially several other nuclear receptor heterodimers.
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http://dx.doi.org/10.1073/pnas.2020551118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817120PMC
January 2021

Systolic Blood Pressure and Risk for Ventricular Arrhythmia in Patients With an Implantable Cardioverter Defibrillator.

Am J Cardiol 2021 03 5;143:74-79. Epub 2021 Jan 5.

Leviev Heart Institute and Sackler School of Medicine Tel Aviv University, Israel. Electronic address:

Low systolic blood pressure (SBP) was previously suggested to be a marker for heart failure and mortality in patients with low left ventricular ejection fraction. We aimed to explore the association of SBP on risk of ventricular tachyarrhythmias (VTA) and atrial arrhythmias as well as appropriate and inappropriate Implantable Cardioverter Defibrillator (ICD) therapy. The study population comprised 1,481 of 1,500 (99%) patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy trial. Multivariate Cox proportional hazards regression modeling was used to identify the association of baseline SBP (recorded prior to ICD implantation) with the risk of VTA > 170 beats/min during follow-up (primary end point) and atrial arrhythmia, appropriate and inappropriate ICD therapy, hospitalization and death (secondary end points). SBP was dichotomized at 120 mm Hg (approximate mean and median) and was also assessed as a continuous measure. Multivariate analysis showed that each 10 mm Hg decrement in SBP was associated with corresponding 11% increased risk for VTA (p = 0.008). Low SBP (≤120 mm Hg) was associated with a significant 58% (p = 0.002) increased risk for VTA ≥170 beats/min; 53% (p = 0.019) increased risk for VTA ≥200 beats/min; and 65% (p = 0.001) increased risk for appropriate ICD therapy, as compared with SBP >120 mm Hg. Low SBP was not associated with increased risk of atrial arrhythmias, and inappropriate ICD therapy. In conclusion, in MADIT-RIT, SBP (≤120 mm Hg) predicted higher rates of VTA. These findings suggest that SBP may be utilized for VTA risk stratification in candidates for primary ICD therapy.
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http://dx.doi.org/10.1016/j.amjcard.2020.12.033DOI Listing
March 2021

Plexus-specific retinal capillary avascular area in exudative age-related macular degeneration with projection-resolved OCT angiography.

Br J Ophthalmol 2020 Dec 22. Epub 2020 Dec 22.

Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA

Objective: To detect the plexus-specific retinal capillary avascular area in exudative age-related macular degeneration (EAMD) with projection-resolved optical coherence tomography angiography (PR-OCTA).

Methods And Analysis: In this prospective cross-sectional single centre study, eyes with treatment-naïve EAMD underwent macular 3×3 mm OCTA with AngioVue system. OCTA scans were analysed and processed including three-dimensional projection artefact removal, retinal layer semi-automated segmentation and en face angiogram generation. Automated quantification of extrafoveal (excluding the central 1 mm circle) avascular area (EAA) were calculated on projection-resolved superficial vascular complex (SVC), intermediate capillary plexus (ICP) and deep capillary plexus (DCP), respectively.

Results: Nineteen eyes with EAMD and 19 age-matched healthy control eyes were included. There was no significant difference between the EAMD and control eyes in terms of age, sex, axial length and mean ocular perfusion pressure (all p>0.05). Compared with control eyes, EAMD eyes had significantly larger EAA in SVC (median 0.125 vs 0.059 mm, p=0.006), ICP (0.016 vs 0.000 mm, p=0.004) and DCP (0.033 vs 0.000 mm, p<0.001).

Conclusion: PR-OCTA showed that EAMD is associated with focal avascular area in all the three retinal vascular plexuses.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317562DOI Listing
December 2020

Potential SARS-CoV-2 protease M inhibitors: repurposing FDA-approved drugs.

Phys Biol 2021 02 9;18(2):025001. Epub 2021 Feb 9.

San Diego Supercomputer Center, UC San Diego, California, Unites States of America.

Using as a template the crystal structure of the SARS-CoV-2 main protease, we developed a pharmacophore model of functional centers of the protease inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of the SARS-CoV-2 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of the protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin-the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.
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http://dx.doi.org/10.1088/1478-3975/abcb66DOI Listing
February 2021

BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia.

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.
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http://dx.doi.org/10.3390/cancers12113353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696913PMC
November 2020

Keratoconus Detection using OCT Corneal and Epithelial Thickness Map Parameters and Patterns.

J Cataract Refract Surg 2020 Nov 19. Epub 2020 Nov 19.

The Center for Ophthalmic Optics and Lasers, Casey Eye Institute, and Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA.

Purpose: To detect keratoconus using optical coherence tomography (OCT) corneal map parameters and patterns.

Setting: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA DESIGN:: Cross-sectional observational study.

Methods: A spectral-domain OCT was used to acquire corneal and epithelial thickness maps in normal, manifest keratoconic, subclinical keratoconic, and forme fruste keratoconic (FFK) eyes. A two-step decision tree was designed. An eye will be classified as keratoconus if both decision tree conditions are met: First, at least one of the four quantitative corneal thickness (minimum, minimum-maximum, superonasal-inferotemporal) and epithelial thickness (standard deviation) map parameters exceed cutoff values. Second, presence of both concentric thinning pattern on the epithelial thickness map and coincident thinning patterns on corneal and epithelial thickness maps by visual inspection.

Results: The study was compromised of 54 eyes from 29 normal participants, 91 manifest keratoconic eyes from 65 patients, 12 subclinical keratoconic eyes from 11 patients, and 19 FFK eyes from 19 patients. The decision tree correctly classified all normal eyes (100% specificity), and had good sensitivities for detecting manifest keratoconus (97.8%), subclinical keratoconus (100.0%), and FFK (73.7%).

Conclusions: The two-step decision tree provided a useful tool to detect keratoconus including cases at early disease stages (subclinical keratoconus and FFK). OCT corneal and epithelial thickness map parameters and patterns can be used in conjunction with topography to improve keratoconus screening.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000498DOI Listing
November 2020

A Coincident Thinning Index for Keratoconus Identification Using OCT Pachymetry and Epithelial Thickness Maps.

J Refract Surg 2020 Nov;36(11):757-765

Purpose: To develop a coincident thinning (CTN) index to differentiate between keratoconic and healthy corneas using optical coherence tomography (OCT) measurements of pachymetry and epithelial thickness.

Methods: Pattern deviation maps of pachymetry and epithelial thickness were generated using Fourier-domain OCT images of the cornea. The co-localized thinning of the two maps was quantified using a novel CTN index, which was calculated from Gaussian fits of the regions of maximum relative thinning. The CTN index was validated using k-fold cross-validation, and its classification performance was compared to minimum pachymetry and maximum keratometry.

Results: A total of 82 normal eyes and 133 eyes within three groups of keratoconus severity were evaluated. The pattern deviation maps for the keratoconic eyes showed relative thinning that was larger in magnitude and more strongly correlated with the Gaussian function compared to normal eyes (all P < .01). The distance between the pachymetric and epithelial maximum relative thinning locations was significantly smaller for the keratoconic eyes than for the normal eyes (all P < .02). The CTN index was significantly larger for all three keratoconus groups compared to normal eyes (all P < .0001). The CTN index demonstrated a sensitivity of 100% in detecting manifest keratoconus, 100% for subclinical keratoconus, and 56% for forme fruste keratoconus. The overall classification accuracy was better for the CTN index (93%) than for minimum pachymetry (86%) and maximum keratometry (86%).

Conclusions: The CTN index is a highly sensitive measure of coincident pachymetric and epithelial thinning. It provides valuable information for detecting and monitoring early to moderate keratoconus. [J Refract Surg. 2020;36(11):757-765.].
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http://dx.doi.org/10.3928/1081597X-20200925-01DOI Listing
November 2020

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Authors:
Wesley H Self Matthew W Semler Lindsay M Leither Jonathan D Casey Derek C Angus Roy G Brower Steven Y Chang Sean P Collins John C Eppensteiner Michael R Filbin D Clark Files Kevin W Gibbs Adit A Ginde Michelle N Gong Frank E Harrell Douglas L Hayden Catherine L Hough Nicholas J Johnson Akram Khan Christopher J Lindsell Michael A Matthay Marc Moss Pauline K Park Todd W Rice Bryce R H Robinson David A Schoenfeld Nathan I Shapiro Jay S Steingrub Christine A Ulysse Alexandra Weissman Donald M Yealy B Taylor Thompson Samuel M Brown Jay Steingrub Howard Smithline Bogdan Tiru Mark Tidswell Lori Kozikowski Sherell Thornton-Thompson Leslie De Souza Peter Hou Rebecca Baron Anthony Massaro Imoigele Aisiku Lauren Fredenburgh Raghu Seethala Lily Johnsky Richard Riker David Seder Teresa May Michael Baumann Ashley Eldridge Christine Lord Nathan Shapiro Daniel Talmor Thomas O’Mara Charlotte Kirk Kelly Harrison Lisa Kurt Margaret Schermerhorn Valerie Banner-Goodspeed Katherine Boyle Nicole Dubosh Michael Filbin Kathryn Hibbert Blair Parry Kendall Lavin-Parsons Natalie Pulido Brendan Lilley Carl Lodenstein Justin Margolin Kelsey Brait Alan Jones James Galbraith Rebekah Peacock Utsav Nandi Taylor Wachs Michael Matthay Kathleen Liu Kirsten Kangelaris Ralph Wang Carolyn Calfee Kimberly Yee Gregory Hendey Steven Chang George Lim Nida Qadir Andrea Tam Rebecca Beutler Joseph Levitt Jenny Wilson Angela Rogers Rosemary Vojnik Jonasel Roque Timothy Albertson James Chenoweth Jason Adams Skyler Pearson Maya Juarez Eyad Almasri Mohamed Fayed Alyssa Hughes Shelly Hillard Ryan Huebinger Henry Wang Elizabeth Vidales Bela Patel Adit Ginde Marc Moss Amiran Baduashvili Jeffrey McKeehan Lani Finck Carrie Higgins Michelle Howell Ivor Douglas Jason Haukoos Terra Hiller Carolynn Lyle Alicia Cupelo Emily Caruso Claudia Camacho Stephanie Gravitz James Finigan Christine Griesmer Pauline Park Robert Hyzy Kristine Nelson Kelli McDonough Norman Olbrich Mark Williams Raj Kapoor Jean Nash Meghan Willig Henry Ford Jayna Gardner-Gray Mayur Ramesh Montefiore Moses Michelle Ng Gong Michael Aboodi Ayesha Asghar Omowunmi Amosu Madeline Torres Savneet Kaur Jen-Ting Chen Aluko Hope Brenda Lopez Kathleen Rosales Jee Young You Jarrod Mosier Cameron Hypes Bhupinder Natt Bryan Borg Elizabeth Salvagio Campbell R Duncan Hite Kristin Hudock Autumn Cresie Faysal Alhasan Jose Gomez-Arroyo Abhijit Duggal Omar Mehkri Andrei Hastings Debasis Sahoo Francois Abi Fadel Susan Gole Valerie Shaner Allison Wimer Yvonne Meli Alexander King Thomas Terndrup Matthew Exline Sonal Pannu Emily Robart Sarah Karow Catherine Hough Bryce Robinson Nicholas Johnson Daniel Henning Monica Campo Stephanie Gundel Sakshi Seghal Sarah Katsandres Sarah Dean Akram Khan Olivia Krol Milad Jouzestani Peter Huynh Alexandra Weissman Donald Yealy Denise Scholl Peter Adams Bryan McVerry David Huang Derek Angus Jordan Schooler Steven Moore Clark Files Chadwick Miller Kevin Gibbs Mary LaRose Lori Flores Lauren Koehler Caryn Morse John Sanders Caitlyn Langford Kristen Nanney Masiku MdalaGausi Phyllis Yeboah Peter Morris Jamie Sturgill Sherif Seif Evan Cassity Sanjay Dhar Marjolein de Wit Jessica Mason Andrew Goodwin Greg Hall Abbey Grady Amy Chamberlain Samuel Brown Joseph Bledsoe Lindsay Leither Ithan Peltan Nathan Starr Melissa Fergus Valerie Aston Quinn Montgomery Rilee Smith Mardee Merrill Katie Brown Brent Armbruster Estelle Harris Elizabeth Middleton Robert Paine Stacy Johnson Macy Barrios John Eppensteiner Alexander Limkakeng Lauren McGowan Tedra Porter Andrew Bouffler J. Clancy Leahy Bennet deBoisblanc Matthew Lammi Kyle Happel Paula Lauto Wesley Self Jonathan Casey Matthew Semler Sean Collins Frank Harrell Christopher Lindsell Todd Rice William Stubblefield Christopher Gray Jakea Johnson Megan Roth Margaret Hays Donna Torr Arwa Zakaria David Schoenfeld Taylor Thompson Douglas Hayden Nancy Ringwood Cathryn Oldmixon Christine Ulysse Richard Morse Ariela Muzikansky Laura Fitzgerald Samuel Whitaker Adrian Lagakos Roy Brower Lora Reineck Neil Aggarwal Karen Bienstock Michelle Freemer Myron Maclawiw Gail Weinmann Laurie Morrison Mark Gillespie Richard Kryscio Daniel Brodie Wojciech Zareba Anne Rompalo Michael Boeckh Polly Parsons Jason Christie Jesse Hall Nicholas Horton Laurie Zoloth Neal Dickert Deborah Diercks

JAMA 2020 12;324(21):2165-2176

Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, Utah.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.

Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.

Design, Setting, And Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.

Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).

Main Outcomes And Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.

Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).

Conclusions And Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Trial Registration: ClinicalTrials.gov: NCT04332991.
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http://dx.doi.org/10.1001/jama.2020.22240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653542PMC
December 2020

Pressure-Induced Enlargement and Ionic Current Rectification in Symmetric Nanopores.

Nano Lett 2020 11 13;20(11):8089-8095. Epub 2020 Oct 13.

Laboratory of Nanoscale Biology, Institute of Bioengineering, School of Engineering, EPFL, 1015 Lausanne, Switzerland.

Nanopores in solid state membranes are a tool able to probe nanofluidic phenomena or can act as a single molecular sensor. They also have diverse applications in filtration, desalination, or osmotic power generation. Many of these applications involve chemical, or hydrostatic pressure differences which act on both the supporting membrane, and the ion transport through the pore. By using pressure differences between the sides of the membrane and an alternating current approach to probe ion transport, we investigate two distinct physical phenomena: the elastic deformation of the membrane through the measurement of strain at the nanopore, and the growth of ionic current rectification with pressure due to pore entrance effects. These measurements are a significant step toward the understanding of the role of elastic membrane deformation or fluid flow on linear and nonlinear transport properties of nanopores.
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http://dx.doi.org/10.1021/acs.nanolett.0c03083DOI Listing
November 2020

Sensorless adaptive-optics optical coherence tomographic angiography.

Biomed Opt Express 2020 Jul 24;11(7):3952-3967. Epub 2020 Jun 24.

Casey Eye Institute, Oregon Health & Science University, Portland, OR 27239, USA.

Optical coherence tomographic angiography (OCTA) can image the retinal blood flow but visualization of the capillary caliber is limited by the low lateral resolution. Adaptive optics (AO) can be used to compensate ocular aberrations when using high numerical aperture (NA), and thus improve image resolution. However, previously reported AO-OCTA instruments were large and complex, and have a small sub-millimeter field of view (FOV) that hinders the extraction of biomarkers with clinical relevance. In this manuscript, we developed a sensorless AO-OCTA prototype with an intermediate numerical aperture to produce depth-resolved angiograms with high resolution and signal-to-noise ratio over a 2 × 2 mm FOV, with a focal spot diameter of 6 µm, which is about 3 times finer than typical commercial OCT systems. We believe these parameters may represent a better tradeoff between resolution and FOV compared to large-NA AO systems, since the spot size matches better that of capillaries. The prototype corrects defocus, astigmatism, and coma using a figure of merit based on the mean reflectance projection of a slab defined with real-time segmentation of retinal layers. AO correction with the ability to optimize focusing in arbitrary retinal depths - particularly the plexuses in the inner retina - could be achieved in 1.35 seconds. The AO-OCTA images showed greater flow signal, signal-to-noise ratio, and finer capillary caliber compared to commercial OCTA. Projection artifacts were also reduced in the intermediate and deep capillary plexuses. The instrument reported here improves OCTA image quality without excessive sacrifice in FOV and device complexity, and thus may have potential for clinical translation.
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http://dx.doi.org/10.1364/BOE.396829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510908PMC
July 2020