Publications by authors named "C Ronald Scott"

3,466 Publications

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SARS-CoV-2 transmission in a Georgia school district - United States, December 2020-January 2021.

Clin Infect Dis 2021 Apr 17. Epub 2021 Apr 17.

COVID-19 Response, CDC, Atlanta, GA, USA.

Background: To inform prevention strategies, we assessed the extent of SARS-CoV-2 transmission and settings in which transmission occurred in a Georgia public school district.

Methods: During December 1, 2020-January 22, 2021, SARS-CoV-2-infected index cases and their close contacts in schools were identified by school and public health officials. For in-school contacts, we assessed symptoms and offered SARS-CoV-2 RT-PCR testing; performed epidemiologic investigations and whole-genome sequencing to identify in-school transmission; and calculated secondary attack rate (SAR) by school setting (e.g., sports, elementary school classroom), index case role (i.e., staff, student), and index case symptomatic status.

Results: We identified 86 index cases and 1,119 contacts, 688 (63.1%) of whom received testing. Fifty-nine (8.7%) of 679 contacts tested positive; 15 (17.4%) of 86 index cases resulted in ≥2 positive contacts. Among 55 persons testing positive with available symptom data, 31 (56.4%) were asymptomatic. Highest SAR were in indoor, high-contact sports settings (23.8%, 95% confidence interval [CI] 12.7, 33.3), staff meetings/lunches (18.2%, CI 4.5-31.8), and elementary school classrooms (9.5%, CI 6.5-12.5). SAR was higher for staff (13.1%, CI 9.0-17.2) versus student index cases (5.8%, CI 3.6-8.0) and for symptomatic (10.9%, CI 8.1-13.9) versus asymptomatic index cases (3.0%, CI 1.0-5.5).

Conclusions: Indoor sports may pose a risk to the safe operation of in-person learning. Preventing infection in staff members, through measures that include COVID-19 vaccination, is critical to reducing in-school transmission. Because many positive contacts were asymptomatic, contact tracing should be paired with testing, regardless of symptoms.
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http://dx.doi.org/10.1093/cid/ciab332DOI Listing
April 2021

CHK2 inhibition provides a strategy to suppress hematological toxicity from PARP inhibitors.

Mol Cancer Res 2021 Apr 16. Epub 2021 Apr 16.

Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute

Cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) experience various side effects, with hematological toxicity being most common. Short term treatment of mice with olaparib resulted in depletion of reticulocytes, B cell progenitors and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen that targeted DNA repair genes in Eµ-Myc pre-B lymphoma cell lines as a way to identify strategies to suppress hematological toxicity from PARPi. The screen revealed that sgRNAs targeting the serine/threonine kinase CHK2 were enriched following olaparib treatment. Genetic or pharmacological inhibition of CHK2 blunted PARPi response in lymphoid and myeloid cell lines, and in primary murine pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short-circuit this response. Cotreatment with a CHK2 inhibitor did not antagonise olaparib response in ovarian cancer cell lines. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs. Implications: We reveal that genetic or pharmacological inhibition of Checkpoint Kinase 2 (CHK2) may offer a way to alleviate the toxic influence of PARP inhibitors in the hematological system.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0791DOI Listing
April 2021

Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2.

Clin Transl Immunology 2021 5;10(4):e1269. Epub 2021 Apr 5.

School of Chemistry and Molecular Biosciences The University of Queensland St Lucia QLD Australia.

Objectives: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 'MF59C.1' (Seqirus, Parkville, Australia).

Methods: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat.

Results: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4 and cytotoxic CD8 T cells . In the Syrian hamster challenge model ( = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level.

Conclusion: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2-8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models.
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http://dx.doi.org/10.1002/cti2.1269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021130PMC
April 2021

Effectiveness of a Weight Loss Program Using Digital Health in Adolescents and Preadolescents.

Child Obes 2021 Apr 6. Epub 2021 Apr 6.

Department of Cardiovascular Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

To identify an efficacious intervention on treating adolescents with overweight and obesity, this might result in health benefits. Adolescents with overweight or obesity aged 10-17 years with BMI percentile ≥85th were included in this historical observational analysis. Subjects used an entirely remote weight loss program combining mobile applications, frequent self-weighing, and calorie restriction with meal replacement. Body weight changes were evaluated at 42, 60, 90, and 120 days using different metrics including absolute body weight, BMI, and BMI z-score. Chi-square or Fisher exact tests (categorical variables) and Student's -test (continuous variables) were used to compare subjects. In total, 2,825 participants, mean age 14.4 ± 2.2 years, (54.8% girls), were included from October 27, 2016, to December 31, 2017, in mainland China; 1355 (48.0%) had a baseline BMI percentile ≥97th. Mean BMI and BMI z-score were 29.20 ± 4.44 kg/m and 1.89 ± 0.42, respectively. At day 120, mean reduction in body weight, BMI, and BMI z-score was 8.6 ± 0.63 kg, 3.13 ± 0.21 kg/m, and 0.42 ± 0.03; 71.4% had lost ≥5% body weight, 69.4% of boys and 73.2% of girls, respectively. Compared with boys, girls achieved greater reduction on BMI z-score at all intervals ( < 0.004 for all comparisons). Higher BMI percentile at baseline and increased frequency of use of the mobile application were directly associated with more significant weight loss. An entirely remote digital weight loss program is effective in facilitating weight loss in adolescents with overweight or obesity in the short term and mid term.
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http://dx.doi.org/10.1089/chi.2020.0317DOI Listing
April 2021

Paediatric non-infectious uveitis in Cape Town, South Africa: a retrospective review of disease characteristics and outcomes on immunomodulating treatment.

Pediatr Rheumatol Online J 2021 Apr 1;19(1):50. Epub 2021 Apr 1.

Department of Paediatric Rheumatology, Red Cross War Memorial Children's Hospital, Klipfontein Rd, Cape Town, 7700, South Africa.

Background: Non-infectious uveitis is a well-reported cause of blindness in more developed countries, however data from sub-Saharan Africa is lacking. Here we aim to describe the diseases associated with paediatric non-infectious uveitis and the effect of currently available treatment in this setting.

Methods: A retrospective observational analysis of children with non-infectious uveitis from January 2010 to December 2017, attending the tertiary paediatric rheumatology and ophthalmology referral units in Cape Town was conducted. Statistical analysis utilising STATA13 software was performed with p < 0.05 considered significant.

Results: Twenty-nine children were identified: median age at first visit of 74 months (IQR 49-86 months), female to male ratio of 0.9:1, predominantly of mixed ancestry (72.4%). Juvenile idiopathic arthritis associated uveitis (JIAU) (48.3%), idiopathic uveitis (41.4%), sarcoidosis (6.9%) and Behcet's disease (3.5%) were diagnosed. Chronic anterior uveitis (72.4%) was the most frequent finding. Fifty-five percent had complications at presentation and all children with idiopathic uveitis presented with cataracts. Only 6.5% of the JIA cohort had JIAU. All JIA children had chronic anterior uveitis. There were no differences between JIA children with uveitis and those without uveitis, for sex (p = 0.68) and race (p = 0.58). Significantly, children with uveitis presented at an overall younger age (p = 0.008), had oligo-articular JIA (p = 0.01) and were antinuclear antibody positive (p < 0.001). Children with idiopathic uveitis were predominantly male (66.6%) with chronic anterior uveitis (41.7%). Nineteen children (65.5%) in the cohort had inactive disease on treatment at 12 months from diagnosis, which included 10 on topical corticosteroid therapy. At the last clinical visit 17 (58.6%) on standard initial therapy, 8 (27.6%) on tumour necrosis factor inhibitors and 2 on additional DMARDs were in remission. Five of these children still required topical corticosteroids. Surgery was performed in 41.4%, primarily in the idiopathic group. Visual acuity improved or was maintained on treatment.

Conclusion: Current practice seems to detect children with potentially sight-threatening disease but the high rate of complications and the low percentage of children with JIAU raises concerns of delayed healthcare intervention. Tumour necrosis factor inhibitors have improved outcomes in refractory cases in this cohort, however further studies are needed.
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http://dx.doi.org/10.1186/s12969-021-00537-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017656PMC
April 2021

Management of low periprosthetic distal femoral fractures.

Bone Joint J 2021 Apr;103-B(4):635-643

Edinburgh Orthopaedics, Royal Infirmary of Edinburgh, Edinburgh, UK.

Aims: Debate continues regarding the optimum management of periprosthetic distal femoral fractures (PDFFs). This study aims to determine which operative treatment is associated with the lowest perioperative morbidity and mortality when treating low (Su type II and III) PDFFs comparing lateral locking plate fixation (LLP-ORIF) or distal femoral arthroplasty (DFA).

Methods: This was a retrospective cohort study of 60 consecutive unilateral (PDFFs) of Su types II (40/60) and III (20/60) in patients aged ≥ 60 years: 33 underwent LLP-ORIF (mean age 81.3 years (SD 10.5), BMI 26.7 (SD 5.5); 29/33 female); and 27 underwent DFA (mean age 78.8 years (SD 8.3); BMI 26.7 (SD 6.6); 19/27 female). The primary outcome measure was reoperation. Secondary outcomes included perioperative complications, calculated blood loss, transfusion requirements, functional mobility status, length of acute hospital stay, discharge destination and mortality. Kaplan-Meier survival analysis was performed. Cox multivariate regression analysis was performed to identify risk factors for reoperation after LLP-ORIF.

Results: Follow-up was at mean 3.8 years (1.0 to 10.4). One-year mortality was 13% (8/60). Reoperation was more common following LLP-ORIF: 7/33 versus 0/27 (p = 0.008). Five-year survival for reoperation was significantly better following DFA; 100% compared to 70.8% (95% confidence interval (CI) 51.8% to 89.8%, p = 0.006). There was no difference for the endpoint mechanical failure (including radiological loosening); ORIF 74.5% (56.3 to 92.7), and DFA 78.2% (52.3 to 100, p = 0.182). Reoperation following LLP-ORIF was independently associated with medial comminution; hazard ratio (HR) 10.7 (1.45 to 79.5, p = 0.020). Anatomical reduction was protective against reoperation; HR 0.11 (0.013 to 0.96, p = 0.046). When inadequately fixed fractures were excluded, there was no difference in five-year survival for either reoperation (p = 0.156) or mechanical failure (p = 0.453).

Conclusion: Absolute reoperation rates are higher following LLP fixation of low PDFFs compared to DFA. Where LLP-ORIF was well performed with augmentation of medial comminution, there was no difference in survival compared to DFA. Though necessary in very low fractures, DFA should be used with caution in patients with greater life expectancies due to the risk of longer term aseptic loosening. Cite this article:  2021;103-B(4):635-643.
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http://dx.doi.org/10.1302/0301-620X.103B4.BJJ-2020-1710.R1DOI Listing
April 2021

The effect of hospital case volume on re-revision following revision total knee arthroplasty.

Bone Joint J 2021 Apr;103-B(4):602-609

Department of Orthopaedics, University of Edinburgh, Edinburgh, UK.

Aims: The aim of this study was to measure the effect of hospital case volume on the survival of revision total knee arthroplasty (RTKA).

Methods: This is a retrospective analysis of Scottish Arthroplasty Project data, a nationwide audit which prospectively collects data on all arthroplasty procedures performed in Scotland. The primary outcome was RTKA survival at ten years. The primary explanatory variable was the effect of hospital case volume per year on RTKA survival. Kaplan-Meier survival curves were plotted with 95% confidence intervals (CIs) to determine the lifespan of RTKA. Multivariate Cox proportional hazards were used to estimate relative revision risks over time. Hazard ratios (HRs) were reported with 95% CI, and p-value < 0.05 was considered statistically significant.

Results: From 1998 to 2019, 8,301 patients (8,894 knees) underwent RTKA surgery in Scotland (median age at RTKA 70 years (interquartile range (IQR) 63 to 76); median follow-up 6.2 years (IQR 3.0 to 10.2). In all, 4,764 (53.6%) were female, and 781 (8.8%) were treated for infection. Of these 8,894 knees, 957 (10.8%) underwent a second revision procedure. Male sex, younger age at index revision, and positive infection status were associated with need for re-revision. The ten-year survival estimate for RTKA was 87.3% (95% CI 86.5 to 88.1). Adjusting for sex, age, surgeon volume, and indication for revision, high hospital case volume was significantly associated with lower risk of re-revision (HR 0.78 (95% CI 0.64 to 0.94, p < 0.001)). The risk of re-revision steadily declined in centres performing > 20 cases per year; risk reduction was 16% with > 20 cases; 22% with > 30 cases; and 28% with > 40 cases. The lowest level of risk was associated with the highest volume centres.

Conclusion: The majority of RTKA in Scotland survive up to ten years. Increasing yearly hospital case volume above 20 cases is independently associated with a significant risk reduction of re-revision. Development of high-volume tertiary centres may lead to an improvement in the overall survival of RTKA. Cite this article:  2021;103-B(4):602-609.
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http://dx.doi.org/10.1302/0301-620X.103B4.BJJ-2020-1901.R1DOI Listing
April 2021

Audit and feedback with or without training in-practice targeting antibiotic prescribing (TiPTAP): a study protocol of a cluster randomised trial in dental primary care.

Implement Sci 2021 Mar 30;16(1):32. Epub 2021 Mar 30.

Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland.

Background: Antimicrobial resistance is an increasingly serious threat to global public health and patient safety. Overuse of antibiotics has aggravated this issue. Around 7% of all antibiotics in Scotland are prescribed by dentists. Audit and feedback has been shown to decrease these prescriptions, but there is evidence that dentists still prescribe unnecessarily. Our aim is to compare the effectiveness of a theory-informed in-practice training session (TiPTAP) in addition to individualised audit and feedback, with audit and feedback alone for reducing antibiotic prescribing by NHS dentists working in NHS primary care dental practices.

Methods: We will conduct a 2-arm parallel cluster randomised trial: out of 228 practices, 114 will be randomised to the theory-informed in-practice training session targeting antibiotic prescribing and individualised audit and feedback; 114 practices will be randomised to audit and feedback alone. The theory-informed session will include (a) an introductory session including several behaviour change techniques; (b) problem solving discussion, setting and recording action plans; (c) practice-level prescribing feedback discussion. The primary outcome is the number of antibiotic items per 100 NHS treatment claims over a 1-year period post-randomisation for each dentist. Secondary outcomes are the number of amoxicillin 3 g and broad spectrum antibiotics prescribed per 100 NHS treatment claims over a 1-year period; amoxicillin 3 g and broad spectrum antibiotics defined daily doses of antibiotics per 100 claims. Process measures include fidelity, knowledge, and confidence. Primary and secondary outcomes will be obtained using routine data.

Discussion: This study provides the opportunity to robustly assess the effect of adding an in-practice training co-intervention to audit and feedback. Its behaviour change theory-informed content will allow replication of the different components and can inform future training interventions.

Trial Registration: ISRCTN, ISRCTN12345678 . Registered 18 June 2020.
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http://dx.doi.org/10.1186/s13012-021-01098-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007384PMC
March 2021

Impact of Radiation Dose on Postoperative Complications in Esophageal and Gastroesophageal Junction Cancers.

Front Oncol 2021 10;11:614640. Epub 2021 Mar 10.

Icahn School of Medicine at Mount Sinai, New York, NY, United States.

The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established. We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy). Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups. In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.
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http://dx.doi.org/10.3389/fonc.2021.614640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987936PMC
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 Cindrić Zlatko Hucika David Ozretic Majda Seferovic Saric Frantiek Pfeifer Igor Karpowic David Cernik Martin Sramek Miroslav Skoda Helena Hlavacova Lukas Klecka Martin Koutny Daniel Vaclavik Ondrej Skoda Jan Fiksa Katerina Hanelova Miroslava Nevsimalova Robert Rezek Petr Prochazka Gabriela Krejstova Jiri Neumann Marta Vachova Henryk Brzezanski David Hlinovsky Dusan Tenora Rene Jura Lubomír Jurák Jan Novak Ales Novak Zdenek Topinka Petr Fibrich Helena Sobolova Ondrej Volny Hanne Krarup Christensen Nicolas Drenck Helle Klingenberg Iversen Claus Z Simonsen Thomas Clement Truelsen Troels Wienecke Riina Vibo Katrin Gross-Paju Toomas Toomsoo Katrin Antsov Francois Caparros Charlotte Cordonnier Maria Dan Jean-Marc Faucheux Laura Mechtouff Omer Eker Emilie Lesaine Basile Ondze Roxane Peres Fernando Pico Michel Piotin Raoul Pop Francois Rouanet Tatuli Gubeladze Mirza Khinikadze Nino Lobjanidze Alexander Tsikaridze Simon Nagel Peter Arthur Ringleb Michael Rosenkranz Holger Schmidt Annahita 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 Alex Brehm Paolo Machi Urs Fischer Jan Gralla Patrik L Michel Marios-Nikos Psychogios Davide Strambo Soma Banerjee Kailash Krishnan Joseph Kwan Asif Butt Luciana Catanese Andrew Demchuk Thalia Field Jennifer Haynes Michael D Hill Houman Khosravani Ariane Mackey Aleksandra Pikula Gustavo Saposnik Courtney Anne Scott Ashkan Shoamanesh Ashfaq Shuaib Samuel Yip Miguel A Barboza Jose Domingo Barrientos Ligia Ibeth Portillo Rivera Fernando Gongora-Rivera Nelson Novarro-Escudero Anmylene Blanco Michael Abraham Diana Alsbrook Dorothea Altschul Anthony J Alvarado-Ortiz Ivo Bach Aamir Badruddin Nobl Barazangi Charmaine Brereton Alicia Castonguay Seemant Chaturvedi Saqib A Chaudhry Hana Choe Jae H Choi Sushrut Dharmadhikari Kinjal Desai Thomas G Devlin Vinodh T Doss Randall Edgell Mark Etherton Mudassir Farooqui Don Frei Dheeraj Gandhi Mikayel Grigoryan Rishi Gupta Ameer E Hassan Johanna Helenius Artem Kaliaev Ritesh Kaushal Priyank Khandelwal Ayaz M Khawaja Naim N Khoury Benny S Kim Dawn O Kleindorfer Feliks Koyfman Vivien H Lee Lester Y Leung Guillermo Linares Italo Linfante Helmi L Lutsep Lisa Macdougall Shailesh Male Amer Malik Hesham Masoud Molly McDermott Brijesh P Mehta Jiangyong Min Manoj Mittal Jane G Morris Sumeet S Multani Fadi Nahab Krishna Nalleballe Claude B Nguyen Roberta Novakovic-White Santiago Ortega-Gutierrez Rahul H Rahangdale Pankajavalli Ramakrishnan Jose Rafael Romero Natalia Rost Aaron Rothstein Sean Ruland Ruchir Shah Malveeka Sharma Brian Silver Marc Simmons Abhishek Singh Amy K Starosciak Sheryl L Strasser Viktor Szeder Mohamed Teleb Jenny P Tsai Barbara Voetsch Oscar Balaguera Virginia A Pujol Lereis Adriana Luraschi Marcele Schettini Almeida Fabricio Buchdid Cardoso Adriana Conforto Leonardo De Deus Silva Luidia Varrone Giacomini Fabricio Oliveira Lima Alexandre L Longo Pedro Sc Magalhães Rodrigo Targa Martins Francisco Mont'alverne Daissy Liliana Mora Cuervo Leticia Costa Rebello Lenise Valler Viviane Flumignan Zetola Pablo M Lavados Victor 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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

Beyond PPE: a mixed qualitative-quantitative study capturing the wider issues affecting doctors' well-being during the COVID-19 pandemic.

BMJ Open 2021 03 22;11(3):e050223. Epub 2021 Mar 22.

Neurology, West Suffolk NHS Foundation Trust, Bury Saint Edmunds, UK

The COVID-19 pandemic has brought unprecedented challenges to the medical workforce. This has put them at increased risk of burnout at a time when levels are already worryingly high in the profession, with recent studies consistently showing that around half of doctors meet the validated criteria for burnout.

Objectives: To understand the wider factors influencing and impacting upon hospital doctors' well-being during the COVID-19 pandemic in England.

Design: Cross-sectional survey and mixed quantitative-qualitative analysis.

Setting: Acute National Health Service (NHS) Foundation Trust in England.

Participants: An online survey was circulated in early June 2020 to all 449 doctors employed by the Trust. 242 doctors completed the survey (54% response rate).

Primary Outcome Measures: Questions assessed occupational details, self-reported changes in physical and mental health, satisfaction with working hours and patterns, availability of personal protective equipment (PPE), medication and facilities, communication and sought to identify areas seen as having a significant effect on doctors' well-being.

Results: 96% of respondents requiring PPE were able to access it. Nearly half of the respondents felt that their mental health had deteriorated since the start of the pandemic. Over a third stated that their physical health had also declined. Issues identified as having a negative impact on doctors included increased workload, redeployment, loss of autonomy, personal issues affecting family members, anxiety around recovery plans, inadequate access to changing and storage facilities and to rest areas that allow for social distancing. Doctors appreciated access to 'calm rooms' that were made available for staff, access to clinical psychology support, free drinks and free car parking on site.

Conclusion: The emerging themes are suggestive of increased burnout risk among doctors during the COVID-19 pandemic and encompass factors well beyond shortage of PPE. Small organisational initiatives and the implementation of changes suggested by survey respondents can have a positive impact on doctors' well-being.
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http://dx.doi.org/10.1136/bmjopen-2021-050223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985981PMC
March 2021

The number of patients "worse than death" while waiting for a hip or knee arthroplasty has nearly doubled during the COVID-19 pandemic.

Bone Joint J 2021 Apr 23;103-B(4):672-680. Epub 2021 Mar 23.

Department of Orthopaedics, Freeman Hospital, Newcastle, UK.

Aims: The aim of this study was to assess the quality of life of patients on the waiting list for a total hip (THA) or knee arthroplasty (KA) during the COVID-19 pandemic. Secondary aims were to assess whether length of time on the waiting list influenced quality of life and rate of deferral of surgery.

Methods: During the study period (August and September 2020) 843 patients (THA n = 394, KA n = 449) from ten centres in the UK reported their EuroQol five dimension (EQ-5D) scores and completed a waiting list questionnaire (2020 group). Patient demographic details, procedure, and date when listed were recorded. Patients scoring less than zero for their EQ-5D score were defined to be in a health state "worse than death" (WTD). Data from a retrospective cohort (January 2014 to September 2017) were used as the control group.

Results: The 2020 group had a significantly worse EQ-5D score compared to the control group for both THA (p < 0.001) and KA (p < 0.001). Over one-third (35.0%, n = 138/394) of patients waiting for a THA and nearly a quarter (22.3%, n = 100/449) for KA were in a health state WTD, which was significantly greater than the control group (odds ratio 2.30 (95% confidence interval (CI) 1.83 to 2.93) and 2.08 (95% CI 1.61 to 2.70), respectively; p < 0.001). Over 80% (n = 680/843) of the 2020 group felt that their quality of life had deteriorated while waiting. Each additional month spent on the waiting list was independently associated with a decrease in quality of life (EQ-5D: -0.0135, p = 0.004). There were 117 (13.9%) patients who wished to defer their surgery and the main reason for this was health concerns for themselves and or their family (99.1%, n = 116/117).

Conclusion: Over one-third of patients waiting for THA and nearly one-quarter waiting for a KA were in a state WTD, which was approaching double that observed prior to the pandemic. Increasing length of time on the waiting list was associated with decreasing quality of life. Level of evidence: Level III retrospective case control study Cite this article: 2021;103-B(4):672-680.
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http://dx.doi.org/10.1302/0301-620X.103B.BJJ-2021-0104.R1DOI Listing
April 2021

Aortic Stenosis Progression, Cardiac Damage, and Survival: Comparison Between Bicuspid and Tricuspid Aortic Valves.

JACC Cardiovasc Imaging 2021 Mar 11. Epub 2021 Mar 11.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Objectives: This study sought to compare aortic stenosis (AS) progression rates, AS-related cardiac damage (AS-CD) indicator incidence and determinants, and survival between patients with tricuspid aortic valve (TAV)-AS and those with bicuspid aortic valve (BAV)-AS.

Background: Differences in AS progression and AS-CD between patients with BAV and patients with TAV are unknown.

Methods: We retrospectively studied consecutive patients with baseline peak aortic valve velocity (peakV) ≥2.5 m/s and left ventricular ejection fraction ≥50%. Follow-up echocardiograms (n = 4,818) provided multiparametric AS progression rates and AS-CD.

Results: The study included 330 BAV (54 ± 14 years) and 581 patients with TAV (72 ± 11 years). At last echocardiogram (median: 5.9 years; interquartile range: 3.9 to 8.5 years), BAV-AS exhibited similar peakV and mean pressure gradient (MPG) as TAV-AS, but larger calculated aortic valve area due to larger aortic annulus (p < 0.0001). Multiparametric progression rates were similar between BAV-AS and TAV-AS (all p ≥ 0.08) and did not predict age-/sex-adjusted survival (p ≥ 0.45). Independent determinants of rapid progression were male sex and baseline AS severity for TAV (all p ≤ 0.024), and age, baseline AS severity, and cardiac risk factors (age interaction: p = 0.02) for BAV (all p ≤ 0.005). At 12 years, patients with TAV-AS had a higher incidence of AS-CD than BAV-AS patients (p < 0.0001), resulting in significantly worse survival compared to BAV-AS (p < 0.0001). AS-CD were independently determined by multiple factors (MPG, age, sex, comorbidities, cardiac function; all p ≤ 0.039), and BAV was independently protective of most AS-CD (all p ≤ 0.05).

Conclusions: In this cohort, TAV-AS and BAV-AS progression rates were similar. Rapid progression did not affect survival and was determined by cardiac risk factors for BAV-AS (particularly in patients with BAV <60 years of age) and unmodifiable factors for TAV-AS. AS-CD and mortality were significantly higher in TAV-AS. Independent determinants of AS-CD were multifactorial, and BAV morphology was AS-CD protective. Therefore, the totality of AS burden (cardiac damage) is clinically crucial for TAV-AS, whereas attention to modifiable risk factors may be preventive for BAV-AS.
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http://dx.doi.org/10.1016/j.jcmg.2021.01.017DOI Listing
March 2021

Molecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: A meta-analysis.

Cancer 2021 Mar 19. Epub 2021 Mar 19.

Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia.

Background: The authors performed a meta-analysis to better quantify the benefit of maintenance poly(ADP-ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum-sensitive, recurrent, high-grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild-type BRCA but homologous recombinant-deficient (HRD), homologous recombinant-proficient (HRP), and baseline clinical prognostic characteristics.

Methods: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression-free survival were pooled across trials using the inverse variance weighted method.

Results: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23-0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17-0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12-0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild-type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31-0.56); and, in those who had wild-type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49-0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab.

Conclusions: In platinum-sensitive, recurrent, high-grade ovarian cancer, maintenance PARPi improves progression-free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.
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http://dx.doi.org/10.1002/cncr.33517DOI Listing
March 2021

National operating volume for primary hip and knee arthroplasty in the COVID-19 era: a study utilizing the Scottish arthroplasty project dataset.

Bone Jt Open 2021 Mar;2(3):203-210

Department of Orthopaedics, University of Edinburgh, Edinburgh, UK.

Aims: The COVID-19 pandemic led to a national suspension of "non-urgent" elective hip and knee arthroplasty. The study aims to measure the effect of the COVID-19 pandemic on total hip arthroplasty (THA) and total knee arthroplasty (TKA) volume in Scotland. Secondary objectives are to measure the success of restarting elective services and model the time required to bridge the gap left by the first period of suspension.

Methods: A retrospective observational study using the Scottish Arthroplasty Project dataset. All patients undergoing elective THAs and TKAs during the period 1 January 2008 to 31 December 2020 were included. A negative binomial regression model using historical case-volume and mid-year population estimates was built to project the future case-volume of THA and TKA in Scotland. The median monthly case volume was calculated for the period 2008 to 2019 (baseline) and compared to the actual monthly case volume for 2020. The time taken to eliminate the deficit was calculated based upon the projected monthly workload and with a potential workload between 100% to 120% of baseline.

Results: Compared to the period 2008 to 2019, primary TKA and THA volume fell by 61.1% and 53.6%, respectively. Since restarting elective services, Scottish hospitals have achieved approximately 40% to 50% of baseline monthly activity. With no changes in current workload, by 2021 there would be a reduction of 9,180 and 10,170 for THA and TKA, respectively. Conversely, working at 120% baseline monthly output, it would take over four years to eliminate the deficit for both TKA and THA.

Conclusion: This national study demonstrates the significant impact that COVID-19 pandemic has had on overall THA and TKA volume. In the six months after resuming elective services, Scottish hospitals averaged less than 50% normal monthly output. Loss of operating capacity will increase treatment delays and likely worsen overall morbidity. Cite this article:  2021;2(3):203-210.
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http://dx.doi.org/10.1302/2633-1462.23.BJO-2020-0193.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009902PMC
March 2021

Association of Daily Alcohol Intake, Volumetric Breast Density, and Breast Cancer Risk.

JNCI Cancer Spectr 2021 Apr 4;5(2):pkaa124. Epub 2021 Feb 4.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided  = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided  > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided  = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.
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http://dx.doi.org/10.1093/jncics/pkaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952225PMC
April 2021

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

J Med Chem 2021 Apr 17;64(7):3658-3676. Epub 2021 Mar 17.

Reviral Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2FX, U.K.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01882DOI Listing
April 2021

ILC3s control splenic cDC homeostasis via lymphotoxin signaling.

J Exp Med 2021 May;218(5)

Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent, Belgium.

The spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα1β2-expressing Rorgt+ ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα+CD4+Esam+ cDC2s, independently of the microbiota and of bone marrow pre-cDC output. Whereas the size of the splenic cDC niche depended on lymphotoxin signaling only during a restricted time frame, the homeostasis of Sirpα+CD4+Esam+ cDC2s required continuous lymphotoxin input. This latter property made Sirpα+CD4+Esam+ cDC2s uniquely susceptible to pharmacological interventions with LTβR agonists and antagonists and to ILC reconstitution strategies. Together, our findings demonstrate that LTα1β2-expressing Rorgt+ ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis.
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http://dx.doi.org/10.1084/jem.20190835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970251PMC
May 2021

Usability of a Digital Registry to Promote Secondary Prevention for Peripheral Artery Disease Patients.

Mayo Clin Proc Innov Qual Outcomes 2021 Feb 28;5(1):94-102. Epub 2020 Nov 28.

Department of Cardiovascular Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN.

Objective: To evaluate usability of a quality improvement tool that promotes guideline-based care for patients with peripheral arterial disease (PAD).

Patients And Methods: The study was conducted from July 19, 2018, to August 21, 2019. We compared the usability of a PAD cohort knowledge solution (CKS) with standard management supported by an electronic health record (EHR). Two scenarios were developed for usability evaluation; the first for the PAD-CKS while the second evaluated standard EHR workflow. Providers were asked to provide opinions about the PAD-CKS tool and to generate a System Usability Scale (SUS) score. Metrics analyzed included time required, number of mouse clicks, and number of keystrokes.

Results: Usability evaluations were completed by 11 providers. SUS for the PAD-CKS was excellent at 89.6. Time required to complete 21 tasks in the CKS was 4 minutes compared with 12 minutes for standard EHR workflow (median,  = .002). Completion of CKS tasks required 34 clicks compared with 148 clicks for the EHR (median,  = .002). Keystrokes for CKS task completion was 8 compared with 72 for EHR (median,  = .004). Providers indicated that overall they found the tool easy to use and the PAD mortality risk score useful.

Conclusions: Usability evaluation of the PAD-CKS tool demonstrated time savings, a high SUS score, and a reduction of mouse clicks and keystrokes for task completion compared to standard workflow using the EHR. Provider feedback regarding the strengths and weaknesses also created opportunities for iterative improvement of the PAD-CKS tool.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930799PMC
February 2021

Introduction of robotic surgery leads to increased rate of segmentectomy in patients with lung cancer.

J Thorac Dis 2021 Feb;13(2):762-767

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, CO, USA.

Background: Pulmonary segmentectomy provides an anatomic lung resection while avoiding removal of excess normal lung tissue. This may be beneficial in patients with minimal pulmonary reserve who present with early-stage non-small cell lung cancer (NSCLC). However, the operative performance of a segmentectomy using a video-assisted thoracoscopic approach can be technically challenging. We hypothesized that introduction of the robotic surgical system would facilitate the performance of a segmentectomy as measured by an increase in the proportion of segmentectomies being pursued.

Methods: We completed a retrospective analysis of thoracoscopic and robotic anatomic lung resections, including lobectomies and segmentectomies, performed in patients with primary lung cancer from the time of initiation of the robotic thoracic surgery program in November 2017 to November 2019. We compared the proportion of thoracoscopic and robotic segmentectomies performed during the first year compared to the second year of the data collection period.

Results: A total of 138 thoracoscopic and robotic anatomic lung resections were performed for primary lung cancer. Types of lung cancer resected (adenocarcinoma, squamous cell carcinoma, or other), tumor size based on clinical T staging (T1-T4), and tumor location were not significantly different between years (P=0.44, P=0.98, and P=0.26, respectively). The proportion of segmentectomies increased from 8.6% during the first year to 25.0% during the second year (P=0.01). One out of 6 (16.7%) segmentectomies were performed using the robot during the first year versus 15 out of 17 (88.2%) during the second year (P=0.003).

Conclusions: Use of the robot led to a significant increase in the number of segmentectomies performed in patients undergoing anatomic lung resection. With increasing lung cancer awareness and widely available screening, a greater number of small, early-stage tumors suitable for segmentectomy will likely be detected. We conclude that robotic-assisted surgery may facilitate the challenges of performing a minimally invasive segmentectomy.
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http://dx.doi.org/10.21037/jtd-20-2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947503PMC
February 2021

Multisite Comparison of MRI Defacing Software Across Multiple Cohorts.

Front Psychiatry 2021 24;12:617997. Epub 2021 Feb 24.

Rotman Research Institute, Baycrest Health Sciences Centre, Toronto, ON, Canada.

With improvements to both scan quality and facial recognition software, there is an increased risk of participants being identified by a 3D render of their structural neuroimaging scans, even when all other personal information has been removed. To prevent this, facial features should be removed before data are shared or openly released, but while there are several publicly available software algorithms to do this, there has been no comprehensive review of their accuracy within the general population. To address this, we tested multiple algorithms on 300 scans from three neuroscience research projects, funded in part by the Ontario Brain Institute, to cover a wide range of ages (3-85 years) and multiple patient cohorts. While skull stripping is more thorough at removing identifiable features, we focused mainly on defacing software, as skull stripping also removes potentially useful information, which may be required for future analyses. We tested six publicly available algorithms (afni_refacer, deepdefacer, mri_deface, mridefacer, pydeface, quickshear), with one skull stripper (FreeSurfer) included for comparison. Accuracy was measured through a pass/fail system with two criteria; one, that all facial features had been removed and two, that no brain tissue was removed in the process. A subset of defaced scans were also run through several preprocessing pipelines to ensure that none of the algorithms would alter the resulting outputs. We found that the success rates varied strongly between defacers, with afni_refacer (89%) and pydeface (83%) having the highest rates, overall. In both cases, the primary source of failure came from a single dataset that the defacer appeared to struggle with - the youngest cohort (3-20 years) for afni_refacer and the oldest (44-85 years) for pydeface, demonstrating that defacer performance not only depends on the data provided, but that this effect varies between algorithms. While there were some very minor differences between the preprocessing results for defaced and original scans, none of these were significant and were within the range of variation between using different NIfTI converters, or using raw DICOM files.
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http://dx.doi.org/10.3389/fpsyt.2021.617997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943842PMC
February 2021

Cardiac Abnormalities in COVID-19 and Relationship to Outcome.

Mayo Clin Proc 2021 04 19;96(4):932-942. Epub 2021 Jan 19.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To characterize the clinical and transthoracic echocardiographic features and 30-day outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19).

Methods: Retrospective cohort study that included consecutive inpatients with COVID-19 infection who underwent clinically indicated transthoracic echocardiography at 10 sites in the Mayo Clinic Health System between March 10 and August 5, 2020. Echocardiography was performed at bedside by cardiac sonographers according to an abbreviated protocol. Echocardiographic results, demographic characteristics, laboratory findings, and clinical outcomes were analyzed.

Results: There were 179 patients, aged 59.8±16.9 years and 111 (62%) men; events within 30 days occurred in 70 (39%) patients, including prolonged hospitalization in 43 (24%) and death in 27 (15%). Echocardiographic abnormalities included left ventricular ejection fraction less than 50% in 29 (16%), regional wall motion abnormalities in 26 (15%), and right ventricular systolic pressure (RVSP) of 35 or greater mm Hg in 44 (44%) of 101 in whom it was measured. Myocardial injury, defined as the presence of significant troponin level elevation accompanied by new ventricular dysfunction or electrocardiographic abnormalities, was present in 13 (7%). Prior echocardiography was available in 36 (20%) patients and pre-existing abnormalities were seen in 28 (78%) of these. In a multivariable age-adjusted model, area under the curve of 0.81, prior cardiovascular disease, troponin level, D-dimer level, and RVSP were related to events at 30 days.

Conclusion: Bedside Doppler assessment of RVSP appears promising for short-term risk stratification in hospitalized patients with COVID-19 infection undergoing clinically indicated echocardiography. Pre-existing echocardiographic abnormalities were common; caution should be exercised in attributing such abnormalities to the COVID-19 infection in this comorbid patient population.
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http://dx.doi.org/10.1016/j.mayocp.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816643PMC
April 2021

Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors.

Cell Death Dis 2021 Mar 12;12(3):268. Epub 2021 Mar 12.

Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.

Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.
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http://dx.doi.org/10.1038/s41419-020-03269-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955127PMC
March 2021

Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.

EMBO Mol Med 2021 Mar 11:e13366. Epub 2021 Mar 11.

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
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http://dx.doi.org/10.15252/emmm.202013366DOI Listing
March 2021

Predicting the risk of developing type 2 diabetes in Chinese people who have coronary heart disease and impaired glucose tolerance.

J Diabetes 2021 Mar 4. Epub 2021 Mar 4.

Diabetes Trials Unit, University of Oxford, Oxford, UK.

Aims: Robust diabetes risk estimates in Asian patients with impaired glucose tolerance (IGT) and coronary heart disease (CHD) are lacking. We developed a Chinese type 2 diabetes risk calculator using Acarbose Cardiovascular Evaluation (ACE) trial data.

Methods: There were 3105 placebo-treated ACE participants with requisite data for model development. Clinically relevant variables, and those showing nominal univariate association with new-onset diabetes (P < .10), were entered into BASIC (clinical variables only), EXTENDED (clinical variables plus routinely available laboratory results), and FULL (all candidate variables) logistic regression models. External validation was performed using the Luzhou prospective cohort of 1088 Chinese patients with IGT.

Results: Over median 5.0 years, 493 (15.9%) ACE participants developed diabetes. Lower age, higher body mass index, and use of corticosteroids or thiazide diuretics were associated with higher diabetes risk. C-statistics for the BASIC (using these variables), EXTENDED (adding male sex, fasting plasma glucose, 2-hour glucose, and HbA1c), and FULL models were 0.610, 0.757, and 0.761 respectively. The EXTENDED model predicted a lower 13.9% 5-year diabetes risk in the Luzhou cohort than observed (35.2%, 95% confidence interval 31.3%-39.5%, C-statistic 0.643).

Conclusion: A risk prediction model using routinely available clinical variables can be used to estimate diabetes risk in Chinese people with CHD and IGT.
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http://dx.doi.org/10.1111/1753-0407.13175DOI Listing
March 2021

Seizure Clusters, Seizure Severity Markers, and SUDEP Risk.

Front Neurol 2021 12;12:643916. Epub 2021 Feb 12.

National Institute of Neurological Disorders and Stroke Center for Sudden Unexpected Death in Epilepsy Research (CSR), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States.

Seizure clusters may be related to Sudden Unexpected Death in Epilepsy (SUDEP). Two or more generalized convulsive seizures (GCS) were captured during video electroencephalography in 7/11 (64%) patients with monitored SUDEP in the MORTEMUS study. It follows that seizure clusters may be associated with epilepsy severity and possibly with SUDEP risk. We aimed to determine if electroclinical seizure features worsen from seizure to seizure within a cluster and possible associations between GCS clusters, markers of seizure severity, and SUDEP risk. Patients were consecutive, prospectively consented participants with drug-resistant epilepsy from a multi-center study. Seizure clusters were defined as two or more GCS in a 24-h period during the recording of prolonged video-electroencephalography in the Epilepsy monitoring unit (EMU). We measured heart rate variability (HRV), pulse oximetry, plethysmography, postictal generalized electroencephalographic suppression (PGES), and electroencephalography (EEG) recovery duration. A linear mixed effects model was used to study the difference between the first and subsequent seizures, with a level of significance set at < 0.05. We identified 112 GCS clusters in 105 patients with 285 seizures. GCS lasted on average 48.7 ± 19 s (mean 49, range 2-137). PGES emerged in 184 (64.6%) seizures and postconvulsive central apnea (PCCA) was present in 38 (13.3%) seizures. Changes in seizure features from seizure to seizure such as seizure and convulsive phase durations appeared random. In grouped analysis, some seizure features underwent significant deterioration, whereas others improved. Clonic phase and postconvulsive central apnea (PCCA) were significantly shorter in the fourth seizure compared to the first. By contrast, duration of decerebrate posturing and ictal central apnea were longer. Four SUDEP cases in the cluster cohort were reported on follow-up. Seizure clusters show variable changes from seizure to seizure. Although clusters may reflect epilepsy severity, they alone may be unrelated to SUDEP risk. We suggest a stochastic nature to SUDEP occurrence, where seizure clusters may be more likely to contribute to SUDEP if an underlying progressive tendency toward SUDEP has matured toward a critical SUDEP threshold.
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http://dx.doi.org/10.3389/fneur.2021.643916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907515PMC
February 2021

High-resolution surface faulting from the 1983 Idaho Lost River Fault M 6.9 earthquake and previous events.

Sci Data 2021 Feb 26;8(1):68. Epub 2021 Feb 26.

DiSPUTer - Dipartimento di Scienze Psicologiche, della Salute e del Territorio, Università G. d'Annunzio Chieti-Pescara, Chieti, Italy.

We present high-resolution mapping and surface faulting measurements along the Lost River fault (Idaho-USA), a normal fault activated in the 1983 (M 6.9) earthquake. The earthquake ruptured ~35 km of the fault with a maximum throw of ~3 m. From new 5 to 30 cm-pixel resolution topography collected by an Unmanned Aerial Vehicle, we produce the most comprehensive dataset of systematically measured vertical separations from ~37 km of fault length activated by the 1983 and prehistoric earthquakes. We provide Digital Elevation Models, orthophotographs, and three tables of: (i) 757 surface rupture traces, (ii) 1295 serial topographic profiles spaced 25 m apart that indicate rupture zone width and (iii) 2053 vertical separation measurements, each with additional textual and numerical fields. Our novel dataset supports advancing scientific knowledge about this fault system, refining scaling laws of intra-continental faults, comparing to other earthquakes to better understand faulting processes, and contributing to global probabilistic hazard approaches. Our methodology can be applied to other fault zones with high-resolution topographic data.
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http://dx.doi.org/10.1038/s41597-021-00838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910603PMC
February 2021

Clusters of SARS-CoV-2 Infection Among Elementary School Educators and Students in One School District - Georgia, December 2020-January 2021.

MMWR Morb Mortal Wkly Rep 2021 Feb 26;70(8):289-292. Epub 2021 Feb 26.

In-person learning benefits children and communities (1). Understanding the context in which transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), occurs in schools is critical to improving the safety of in-person learning. During December 1, 2020-January 22, 2021, Cobb and Douglas Public Health (CDPH), the Georgia Department of Public Health (GDPH), and CDC investigated SARS-CoV-2 transmission in eight public elementary schools in a single school district. COVID-19 cases* among educators and students were either self-reported or identified by local public health officials. Close contacts (contacts) of persons with a COVID-19 case received testing. Among contacts who received positive test results, public health investigators assessed epidemiologic links, probable transmission directionality, and the likelihood of in-school transmission. Nine clusters of three or more epidemiologically linked COVID-19 cases were identified involving 13 educators and 32 students at six of the eight elementary schools. Two clusters involved probable educator-to-educator transmission that was followed by educator-to-student transmission and resulted in approximately one half (15 of 31) of school-associated cases. Sixty-nine household members of persons with school-associated cases were tested, and 18 (26%) received positive results. All nine transmission clusters involved less than ideal physical distancing, and five involved inadequate mask use by students. Educators were central to in-school transmission networks. Multifaceted mitigation measures in schools, including promotion of COVID-19 precautions outside of school, minimizing in-person adult interactions at school, and ensuring universal and correct mask use and physical distancing among educators and students when in-person interaction is unavoidable, are important in preventing in-school transmission of SARS-CoV-2. Although not required for reopening schools, COVID-19 vaccination should be considered as an additional mitigation measure to be added when available.
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http://dx.doi.org/10.15585/mmwr.mm7008e4DOI Listing
February 2021