Publications by authors named "J Merlijn van den Berg"

3,327 Publications

  • Page 1 of 1

Aspirin Alone Versus Dual Antiplatelet Therapy After Transcatheter Aortic Valve Implantation: A Systematic Review and Patient-Level Meta-Analysis.

J Am Heart Assoc 2021 Apr 16:e019604. Epub 2021 Apr 16.

Department of Cardiology St. Antonius Hospital Nieuwegein The Netherlands.

Background In patients undergoing transcatheter aortic valve implantation without an indication for oral anticoagulation, it is unclear whether single or dual antiplatelet therapy (DAPT) is necessary to minimize both the bleeding and thromboembolic risk. In this patient-level meta-analysis, we further investigate the effect of aspirin alone compared with DAPT for preventing both thromboembolic and bleeding events after transcatheter aortic valve implantation. Methods and Results We conducted a systematic review of all available randomized controlled trials comparing aspirin with DAPT. In total, 1086 patients were included across 4 eligible trials. The primary outcomes were the composite of all-cause mortality, major or life-threatening bleeding, stroke or myocardial infarction (first composite outcome), and the same composite excluding bleeding (second composite outcome), both tested at 30 days and 3 months. The first composite outcome occurred significantly less in the aspirin-alone group at 30 days (10.3% versus 14.7%, odds ratio [OR], 0.67; 95% CI, 0.46-0.97, =0.034) and 3 months (11.0% versus 16.5%, hazard ratio [HR], 0.66; 95% CI, 0.47-0.94, =0.02), compared with the DAPT group. The second composite outcome occurred in 5.5% and 6.6% at 30 days (OR, 0.83; 95% CI, 0.50-1.38, =0.47) and in 6.9% and 8.5% at 3 months in the aspirin-alone group compared with the DAPT group (HR, 0.82; 95% CI, 0.52-1.29, =0.39), respectively. Conclusions In patients without an indication for oral anticoagulation undergoing transcatheter aortic valve implantation, aspirin alone significantly reduced the composite of thromboembolic and bleeding events, and does not increase the composite of thromboembolic events after transcatheter aortic valve implantation, compared with DAPT.
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http://dx.doi.org/10.1161/JAHA.120.019604DOI Listing
April 2021

Trauma mechanism and patient reported outcome in tibial plateau fractures with posterior involvement.

Knee 2021 Apr 10;30:41-50. Epub 2021 Apr 10.

Dept. Trauma Surgery, University Hospital Leuven, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address:

Introduction: Posterior tibial plateau fractures (PTPF) have a high impact on functional outcome and the optimal treatment strategy is not well established. The goal of this study was to assess the relationship between trauma mechanism, fracture morphology and functional outcome in a large multicenter cohort and define possible strategies to improve the outcome.

Methods: An international retrospective cohort study was conducted in five level-1 trauma centers. All consecutive operatively treated PTPF were evaluated. Preoperative imaging was reviewed to determine the trauma mechanism. Patient reported outcome was scored using the Knee injury and Osteoarthritis Outcome Score (KOOS).

Results: A total of 145 tibial plateau fractures with posterior involvement were selected with a median follow-up of 32.2 months (IQR 24.1-43.2). Nine patients (6%) sustained an isolated posterior fracture. Seventy-two patients (49%) sustained a two-column fracture and three-column fractures were diagnosed in 64 (44%) patients. Varus trauma was associated with poorer outcome on the 'symptoms' (p = 0.004) and 'pain' subscales (p = 0.039). Delayed-staged surgery was associated with worse outcome scores for all subscales except 'pain'. In total, 27 patients (18%) were treated with posterior plate osteosynthesis without any significant difference in outcome.

Conclusions: Fracture morphology, varus trauma mechanism and delayed-staged surgery (i.e. extensive soft-tissue injury) were identified as important prognostic factors on postoperative outcome in PTPF. In order to assess possible improvement of outcome, future studies with routine preoperative MRI to assess associated ligamentous injury in tibial plateau fractures (especially for varus trauma) are needed.
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http://dx.doi.org/10.1016/j.knee.2021.03.011DOI Listing
April 2021

Impact of chromatin context on Cas9-induced DNA double-strand break repair pathway balance.

Mol Cell 2021 Apr 6. Epub 2021 Apr 6.

Oncode Institute, Netherlands Cancer Institute, 1066 CX, Amsterdam, the Netherlands; Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX, Amsterdam, the Netherlands; Department of Cell Biology, Erasmus University Medical Centre, 3015 CN, Rotterdam, the Netherlands. Electronic address:

DNA double-strand break (DSB) repair is mediated by multiple pathways. It is thought that the local chromatin context affects the pathway choice, but the underlying principles are poorly understood. Using a multiplexed reporter assay in combination with Cas9 cutting, we systematically measure the relative activities of three DSB repair pathways as a function of chromatin context in >1,000 genomic locations. This reveals that non-homologous end-joining (NHEJ) is broadly biased toward euchromatin, while the contribution of microhomology-mediated end-joining (MMEJ) is higher in specific heterochromatin contexts. In H3K27me3-marked heterochromatin, inhibition of the H3K27 methyltransferase EZH2 reverts the balance toward NHEJ. Single-stranded template repair (SSTR), often used for precise CRISPR editing, competes with MMEJ and is moderately linked to chromatin context. These results provide insight into the impact of chromatin on DSB repair pathway balance and guidance for the design of Cas9-mediated genome editing experiments.
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http://dx.doi.org/10.1016/j.molcel.2021.03.032DOI Listing
April 2021

Incidence, predictors, and outcomes associated with acute kidney injury in patients undergoing transcatheter aortic valve replacement: from the BRAVO-3 randomized trial.

Clin Res Cardiol 2021 Apr 11. Epub 2021 Apr 11.

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

Background: Acute kidney injury (AKI) is not uncommon in patients undergoing transcatheter aortic valve replacement (TAVR).

Objective: We examined the incidence, predictors, and outcomes of AKI from the BRAVO 3 randomized trial.

Methods: The BRAVO-3 trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin vs. unfractionated heparin (UFH). The primary endpoint of the trial was Bleeding Academic Research Consortium (BARC) type ≥ 3b bleeding at 48 h. Total follow-up was to 30 days. AKI was adjudicated using the modified RIFLE (Valve Academic Research Consortium, VARC 1) criteria through 30-day follow-up, and in a sensitivity analysis AKI was assessed at 7 days (modified VARC-2 criteria). We examined the incidence, predictors, and 30-day outcomes associated with diagnosis of AKI. We also examined the effect of procedural anticoagulant (bivalirudin or unfractionated heparin, UFH) on AKI within 48 h after TAVR.

Results: The trial population had a mean age of 82.3 ± 6.5 years including 48.8% women with mean EuroScore I 17.05 ± 10.3%. AKI occurred in 17.0% during 30-day follow-up and was associated with greater adjusted risk of 30-day death (13.0% vs. 3.5%, OR 5.84, 95% CI 2.62-12.99) and a trend for more BARC ≥ 3b bleeding (15.1% vs. 8.6%, OR 1.80, 95% CI 0.99-3.25). Predictors of 30-day AKI were baseline hemoglobin, body weight, and pre-existing coronary disease. AKI occurred in 10.7% at 7 days and was associated with significantly greater risk of 30-day death (OR 6.99, 95% CI 2.85-17.15). Independent predictors of AKI within 7 days included pre-existing coronary or cerebrovascular disease, chronic kidney disease (CKD), and transfusion which increased risk, whereas post-dilation was protective. The incidence of 48-h AKI was higher with bivalirudin compared to UFH in the intention to treat cohort (10.9% vs. 6.5%, p = 0.03), but not in the per-protocol assessment (10.7% vs. 7.1%, p = 0.08).

Conclusion: In the BRAVO 3 trial, AKI occurred in 17% at 30 days and in 10.7% at 7 days. AKI was associated with a significantly greater adjusted risk for 30-day death. Multivariate predictors of AKI at 30 days included baseline hemoglobin, body weight, and prior coronary artery disease, and predictors at 7 days included pre-existing vascular disease, CKD, transfusion, and valve post-dilation. Bivalirudin was associated with greater AKI within 48 h in the intention to treat but not in the per-protocol analysis.
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http://dx.doi.org/10.1007/s00392-020-01787-7DOI Listing
April 2021

Increased complement activation 3 to 6 h after trauma is a predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome: a prospective observational study.

Mol Med 2021 04 8;27(1):35. Epub 2021 Apr 8.

Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.

Background: Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome.

Methods: In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients' admission TCC, TCC-AUC, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures.

Results: TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC correlated positively with New Injury Severity Score (Spearman's rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (- 0.21, 0.02 and - 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC were negatively associated with ventilator-free days. TCC-AUC outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4.

Conclusions: Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.
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http://dx.doi.org/10.1186/s10020-021-00286-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028580PMC
April 2021

Evaluation of Dual Versus Triple Therapy by Landmark Analysis in the RE-DUAL PCI Trial.

JACC Cardiovasc Interv 2021 Apr;14(7):768-780

Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: The aim of this study was to explore the early versus late benefits and risks of dabigatran dual therapy versus warfarin triple therapy in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.

Background: Patients with atrial fibrillation who undergo percutaneous coronary intervention are at increased risk for both bleeding and thrombotic events.

Methods: A total of 2,725 patients with atrial fibrillation underwent percutaneous coronary intervention and were randomized to receive dabigatran 110 mg, or dabigatran 150 mg plus a P2Y inhibitor (and no aspirin), or warfarin plus a P2Y inhibitor plus aspirin. Landmark analysis was performed at 30 and 90 days.

Results: There was a consistent and large reduction in major or clinically relevant nonmajor bleeding in patients randomized to dual therapy during the first 30 days (110 mg: hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.31 to 0.66; p < 0.0001; 150 mg: HR: 0.46; 95% CI: 0.30 to 0.72; p = 0.0006) compared with warfarin triple therapy. There was early net clinical benefit in both dabigatran groups versus warfarin (110 mg: HR: 0.65; 95% CI: 0.47 to 0.88; p = 0.0062; 150 mg: HR: 0.54; 95% CI: 0.37 to 0.79; p = 0.0015), due to larger reductions in bleeding than increased thrombotic events for dabigatran 110 mg and bleeding reduction without increased thrombotic risk for dabigatran 150 mg dual therapy versus warfarin triple therapy. After the removal of aspirin in the warfarin group, bleeding remained lower with dabigatran 110 mg and was similar with dabigatran 150 mg versus warfarin.

Conclusions: In RE-DUAL PCI, in which patients in the dual-therapy arms were treated with aspirin for an average of only 1.6 days, there was early net clinical benefit with both doses of dabigatran dual therapy, without an increase in thrombotic events with dabigatran 150 mg. This could be helpful in the subset of patients with elevated risk for both bleeding and thrombotic events.
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http://dx.doi.org/10.1016/j.jcin.2021.02.022DOI Listing
April 2021

Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease.

Eur Heart J 2021 Apr 5. Epub 2021 Apr 5.

Department of Cardiology, Ludwig-Maximilians-Universität München (LMU Munich), Munich, Germany.

Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.
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http://dx.doi.org/10.1093/eurheartj/ehab196DOI Listing
April 2021

Assessment of Isochromosome 12p & 12p Abnormalities in Germ Cell Tumors Using FISH, SNP-Arrays & NGS/ Mate-Pair Sequencing.

Hum Pathol 2021 Mar 30. Epub 2021 Mar 30.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;. Electronic address:

The identification of isochromosome 12p [i(12p)] and 12p gains have significant clinical utility in the diagnosis of germ cell tumors (GCT). We have summarized the results of FISH assays to identify i(12p), performed in a Clinical Laboratory Improvement Amendments (CLIA)-validated setting for 536 specimens. In addition, the American Association for Cancer Research (AACR) Project GENIE registry & The Cancer Genome Atlas (TCGA) datasets were evaluated for chromosome 12p gains, and a limited number of cases were concurrently evaluated using FISH, SNP-arrays and NGS (including mate-pair sequencing). Specimens submitted for FISH testing were frequently from potential sites of metastases (male: 70.9%; female: 69.3%) and polysomy of chromosome 12 with or without concurrent i(12p) was a frequent finding, seen in 3% (16 of 536) and 35% (186 of 536) of cases, respectively. Our analysis suggests that 12p gains are likely present in approximately 73% of male GCT, and in 32% of female GCT (AACR GENIE, n=555). When comparing TCGA cases of testicular GCT (n=149) to combined cases of sarcoma, colorectal, prostate, and urothelial carcinoma (n=1754), 12p gains had a sensitivity of 77.2% and specificity of 97.3% for GCT. Some advantages of FISH over SNP-arrays/NGS include relatively lower cost, rapid turnaround time, the ability to analyze biopsy material with a limited number of tumor cells (50 cells), and the ability to distinguish i(12p) from polysomy. The ability to spatially restrict analysis to cells of interest is critical, as specimens submitted for testing often have low tumor purity. Disadvantages include false negative results due to an inability to detect segmental gains due to FISH probe design. With the availability of numerous testing modalities including FISH, SNP-arrays and NGS-based assays, a nuanced understanding of the advantages and disadvantages of each methodology, as has been presented in this study, may inform appropriate testing strategies.
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http://dx.doi.org/10.1016/j.humpath.2021.03.008DOI Listing
March 2021

Cancer Yield Exceeds 2% for BI-RADS 3 Probably Benign Findings in Women Older Than 60 Years in the National Mammography Database.

Radiology 2021 Mar 30:204031. Epub 2021 Mar 30.

From the Department of Radiology, New York University Langone Medical Center, 765 Stewart Ave, Garden City, NY 11530 (C.S.L.); Departments of Computational and Systems Biology (J.M.B.) and Radiology (W.A.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; and Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pa (W.A.B.).

Background Breast Imaging Reporting and Data System (BI-RADS) category 3 (BR3) (probably benign) mammographic assessments are reserved for imaging findings known to have likelihood of malignancy of 2% or less. Purpose To determine the effect of age, finding type, and prior mammography on cancer yield for BR3 findings in the National Mammography Database (NMD). Materials and Methods This HIPAA-compliant retrospective cohort institutional review board-exempt study evaluated women recalled from screening mammography followed by BR3 assessment at diagnostic evaluation from January 2009 to March 2018 and from 471 NMD facilities. Only the first BR3 occurrence was included for women with biopsy or imaging follow-up of at least 2 years. Women with a history of breast cancer or who underwent biopsy at time of initial BR3 assessment were excluded. Women were stratified by age in 10-year intervals. Cancer yield was calculated for each age group, with (for presumed new findings) and without prior mammographic comparison, and by lesion type, where available. Linear regression with weighted-age binning was performed to assess for differences between groups; < .05 was indicative of a significant difference. Results A total of 1 380 652 (18.2%) women were recalled after screening mammography, of whom 157 130 (11.4%) were given a BR3 assessment within 90 days after screening. Of these, 43 628 women (median age, 55 years; age range, 25-90 years) had adequate follow-up for analysis. Cancer yield increased with increasing age decile, ranging from 0.51% (six of 1167) in women aged 30-39 years to 4.63% (41 of 885) in women aged 80-90 years; cancer yield exceeded 2% at and after age 59.7 years for baseline findings and at and after age 53.6 years for presumed new findings, although there was no effect on stage distribution. Cancer yield for baseline BR3 masses was 10 of 2111 (0.47% [95% CI: 0.24, 0.90]) versus 47 of 3003 (1.57% [95% CI: 1.16, 2.09]) with prior comparisons ( < .001); cancer yield for baseline calcifications was eight of 929 (0.86% [95% CI: 0.40, 1.76]) versus 84 of 2999 (2.80% [95% CI: 2.23, 3.47]) with prior comparisons ( < .001). Difference in cancer yield was 0.51% (95% CI: 0.16, 0.86) between women with and women without prior comparison at the same age ( = .006). Conclusion Cancer yield exceeded the 2% threshold for women aged 60 years or older and reached 4.6% for women aged 80-89 years. Breast Imaging Reporting and Data System 3 findings in women with a prior comparison had higher cancer yield than in those without a prior comparison at the same age. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021204031DOI Listing
March 2021

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Authors:
Sarah E Sheppard Ian M Campbell Margaret H Harr Nina Gold Dong Li Hans T Bjornsson Julie S Cohen Jill A Fahrner Ali Fatemi Jacqueline R Harris Catherine Nowak Cathy A Stevens Katheryn Grand Margaret Au John M Graham Pedro A Sanchez-Lara Miguel Del Campo Marilyn C Jones Omar Abdul-Rahman Fowzan S Alkuraya Jennifer A Bassetti Katherine Bergstrom Elizabeth Bhoj Sarah Dugan Julie D Kaplan Nada Derar Karen W Gripp Natalie Hauser A Micheil Innes Beth Keena Neslida Kodra Rebecca Miller Beverly Nelson Malgorzata J Nowaczyk Zuhair Rahbeeni Shay Ben-Shachar Joseph T Shieh Anne Slavotinek Andrew K Sobering Mary-Alice Abbott Dawn C Allain Louise Amlie-Wolf Ping Yee Billie Au Emma Bedoukian Geoffrey Beek James Barry Janet Berg Jonathan A Bernstein Cheryl Cytrynbaum Brian Hon-Yin Chung Sarah Donoghue Naghmeh Dorrani Alison Eaton Josue A Flores-Daboub Holly Dubbs Carolyn A Felix Chin-To Fong Jasmine Lee Fong Fung Balram Gangaram Amy Goldstein Rotem Greenberg Thoa K Ha Joseph Hersh Kosuke Izumi Staci Kallish Elijah Kravets Pui-Yan Kwok Rebekah K Jobling Amy E Knight Johnson Jessica Kushner Bo Hoon Lee Brooke Levin Kristin Lindstrom Kandamurugu Manickam Rebecca Mardach Elizabeth McCormick D Ross McLeod Frank D Mentch Kelly Minks Colleen Muraresku Stanley F Nelson Patrizia Porazzi Pavel N Pichurin Nina N Powell-Hamilton Zoe Powis Alyssa Ritter Caleb Rogers Luis Rohena Carey Ronspies Audrey Schroeder Zornitza Stark Lois Starr Joan Stoler Pim Suwannarat Milen Velinov Rosanna Weksberg Yael Wilnai Neda Zadeh Dina J Zand Marni J Falk Hakon Hakonarson Elaine H Zackai Fabiola Quintero-Rivera

Am J Med Genet A 2021 Mar 30. Epub 2021 Mar 30.

Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
March 2021

Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making.

Genome Med 2021 Mar 29;13(1):50. Epub 2021 Mar 29.

Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.

Background: Newborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates.

Methods: We examined genes listed on four commercial laboratory genomic screening panels for neonates and assessed their clinical actionability using an established age-based semi-quantitative metric to categorize them. We identified genes that were included on multiple panels or distinct between panels.

Results: Three hundred and nine genes appeared on one or more commercial panels: 74 (23.9%) genes were included in all four commercial panels, 45 (14.6%) were on only three panels, 76 (24.6%) were on only two panels, and 114 (36.9%) genes were listed on only one of the four panels. Eighty-two genes (26.5%) listed on one or more panels were assessed by our method to be inappropriate for newborn screening and to require additional parental decision-making. Conversely, 249 genes that we previously identified as being highly actionable were not listed on any of the four commercial laboratory genomic screening panels.

Conclusions: Commercial neonatal genomic screening panels have heterogeneous content and may contain some conditions with lower actionability than would be expected for public health newborn screening; conversely, some conditions with higher actionability may be omitted from these panels. The lack of transparency about how conditions are selected suggests a need for greater detail about panel content in order for parents to make informed decisions. The nuanced activity of gene list selection for genomic screening should be iteratively refined with evidence-based approaches to provide maximal benefit and minimal harm to newborns.
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http://dx.doi.org/10.1186/s13073-021-00867-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008582PMC
March 2021

Patient-Derived Organoid Models of Human Neuroendocrine Carcinoma.

Front Endocrinol (Lausanne) 2021 11;12:627819. Epub 2021 Mar 11.

Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a poorly understood disease with limited treatment options. A better understanding of this disease would greatly benefit from the availability of representative preclinical models. Here, we present the potential of tumor organoids, three-dimensional cultures of tumor cells, to model GEP-NEC. We established three GEP-NEC organoid lines, originating from the stomach and colon, and characterized them using DNA sequencing and immunohistochemistry. Organoids largely resembled the original tumor in expression of synaptophysin, chromogranin and Ki-67. Models derived from tumors containing both neuroendocrine and non-neuroendocrine components were at risk of overgrowth by non-neuroendocrine tumor cells. Organoids were derived from patients treated with cisplatin and everolimus and for the three patients studied, organoid chemosensitivity paralleled clinical response. We demonstrate the feasibility of establishing NEC organoid lines and their potential applications. Organoid culture has the potential to greatly extend the repertoire of preclinical models for GEP-NEC, supporting drug development for this difficult-to-treat tumor type.
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http://dx.doi.org/10.3389/fendo.2021.627819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991829PMC
March 2021

Diagnostic performance and clinical implications for enhancing a hybrid quantitative flow ratio-FFR revascularization decision-making strategy.

Sci Rep 2021 Mar 19;11(1):6425. Epub 2021 Mar 19.

Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.

Invasive fractional flow reserve (FFR) adoption remains low mainly due to procedural and operator related factors as well as costs. Alternatively, quantitative flow ratio (QFR) achieves a high accuracy mainly outside the intermediate zone without the need for hyperaemia and wire-use. We aimed to determine the diagnostic performance of QFR and to evaluate a QFR-FFR hybrid strategy in which FFR is measured only in the intermediate zone. This retrospective study included 289 consecutive patients who underwent invasive coronary angiography and FFR. QFR was calculated for all vessels in which FFR was measured. The QFR-FFR hybrid approach was modelled using the intermediate zone of 0.77-0.87 in which FFR-measurements are recommended. The sensitivity, specificity, and accuracy on a per vessel-based analysis were 84.6%, 86.3% and 85.6% for QFR and 88.0%, 92.9% and 90.3% for the QFR-FFR hybrid approach. The diagnostic accuracy of QFR-FFR hybrid strategy with invasive FFR measurement was 93.4% and resulted in a 56.7% reduction in the need for FFR. QFR has a good correlation and agreement with invasive FFR. A hybrid QFR-FFR approach could extend the use of QFR and reduces the proportion of invasive FFR-measurements needed while improving accuracy.
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http://dx.doi.org/10.1038/s41598-021-85933-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979768PMC
March 2021

Impact of renin-angiotensin system inhibitors on mortality during the COVID Pandemic among STEMI patients undergoing mechanical reperfusion: Insight from an international STEMI registry.

Biomed Pharmacother 2021 Mar 16;138:111469. Epub 2021 Mar 16.

Division of Cardiology, Ospedale degli Infermi, ASL Biella, Italy.

Background: Concerns have been raised on a potential interaction between renin-angiotensin system inhibitors (RASI) and the susceptibility to coronavirus disease 2019 (COVID-19). No data have been so far reported on the prognostic impact of RASI in patients suffering from ST-elevation myocardial infarction (STEMI) during COVID-19 pandemic, which was the aim of the present study.

Methods: STEMI patients treated with primary percutaneous coronary intervention (PPCI) and enrolled in the ISACS-STEMI COVID-19 registry were included in the present sub-analysis and divided according to RASI therapy at admission.

Results: Our population is represented by 6095 patients, of whom 3654 admitted in 2019 and 2441 in 2020. No difference in the prevalence of SARSCoV2 infection was observed according to RASI therapy at admission (2.5% vs 2.1%, p = 0.5), which was associated with a significantly lower mortality (adjusted OR [95% CI]=0.68 [0.51-0.90], P = 0.006), confirmed in the analysis restricted to 2020 (adjusted OR [95% CI]=0.5[0.33-0.74], P = 0.001). Among the 5388 patients in whom data on in-hospital medication were available, in-hospital RASI therapy was associated with a significantly lower mortality (2.1% vs 16.7%, OR [95% CI]=0.11 [0.084-0.14], p < 0.0001), confirmed after adjustment in both periods. Among the 62 SARSCoV-2 positive patients, RASI therapy, both at admission or in-hospital, showed no prognostic effect.

Conclusions: This is the first study to investigate the impact of RASI therapy on the prognosis and SARSCoV2 infection of STEMI patients undergoing PPCI during the COVID-19 pandemic. Both pre-admission and in-hospital RASI were associated with lower mortality. Among SARSCoV2-positive patients, both chronic and in-hospital RASI therapy showed no impact on survival.
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http://dx.doi.org/10.1016/j.biopha.2021.111469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962982PMC
March 2021

Association between multimodality measures of aortic stenosis severity and quality-of-life improvement outcomes after transcatheter aortic valve replacement.

Eur Heart J Qual Care Clin Outcomes 2021 Mar 5. Epub 2021 Mar 5.

Department of Cardiovascular and Thoracic Surgery, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY 11030, USA.

Aims: Up to 40% of patients with aortic stenosis (AS) present with discordant grading of AS severity based on common transthoracic echocardiography (TTE) measures. Our aim was to evaluate the utility of TTE and multi-detector computed tomography (MDCT) measures in predicting symptomatic improvement in patients with AS undergoing transcatheter aortic valve replacement (TAVR).

Methods And Results: A retrospective review of 201 TAVR patients from January 2017 to November 2018 was performed. Pre- and post-intervention quality-of-life was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Pre-intervention measures including dimensionless index (DI), stroke volume index (SVI), mean transaortic gradient, peak transaortic velocity, indexed aortic valve area (AVA), aortic valve calcium score, and AVA based on hybrid MDCT-Doppler calculations were obtained and correlated with change in KCCQ-12 at 30-day follow-up. Among the 201 patients studied, median KCCQ-12 improved from 54.2 pre-intervention to 85.9 post-intervention. In multivariable analysis, patients with a mean gradient >40 mmHg experienced significantly greater improvement in KCCQ-12 at follow-up than those with mean gradient ≤40 mmHg (28.1 vs. 16.4, P = 0.015). Patients with MDCT-Doppler-calculated AVA of ≤1.2 cm2 had greater improvements in KCCQ-12 scores than those with computed tomography-measured AVA of >1.2 cm2 (23.4 vs. 14.1, P = 0.049) on univariate but not multivariable analysis. No association was detected between DI, SVI, peak velocity, calcium score, or AVA index and change in KCCQ-12.

Conclusion: Mean transaortic gradient is predictive of improvement in quality-of-life after TAVR. This measure of AS severity may warrant greater relative consideration when selecting the appropriateness of patients for TAVR.
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http://dx.doi.org/10.1093/ehjqcco/qcab017DOI Listing
March 2021

Clopidogrel Versus Ticagrelor or Prasugrel After Primary Percutaneous Coronary Intervention According to CYP2C19 Genotype: A POPular Genetics Subanalysis.

Circ Cardiovasc Interv 2021 Mar 16:CIRCINTERVENTIONS120009434. Epub 2021 Mar 16.

Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands (D.M.F.C., T.O.B., G.J.A.V., P.W.A.J., J.C.K., B.K.M., J.M.t.B.).

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a genotype-guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y inhibitor treatment in specific genetic subgroups is still a subject of debate.

Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel-treated patients, irrespective of genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months.

Results: A total of 2429 patients were used for analyses. In the first analysis, the *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45-2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48-1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56-0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68-1.90]).

Conclusions: In patients with primary PCI not carrying a loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the *17 polymorphism.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/; Unique identifier: NL2872.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009434DOI Listing
March 2021

Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M trial): A double-blind placebo-controlled randomised trial.

EClinicalMedicine 2021 Feb 6;32:100716. Epub 2021 Jan 6.

Department of Obstetrics and Gynaecology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.

Background: Worldwide, millions of women seek treatment for early pregnancy loss (EPL) annually. Medical management with misoprostol is widely used, but only effective 60% of the time. Pre-treatment with mifepristone prior to misoprostol might improve the success rate of medical management.

Methods: This was a multi-centre, double-blind, placebo-controlled randomised trial in 17 Dutch hospitals. Women with a non-viable pregnancy between 6 and 14 weeks of gestation were eligible for inclusion after at least one week of expectant management. Participants were randomised (1:1) between oral mifepristone 600 mg or an oral placebo tablet. Participants took 400 μg misoprostol orally, repeated after four hours on day two and, if necessary, day three. Primary outcome was expulsion of gestational sac and endometrial thickness <15 mm after 6-8 weeks. Analyses were done according to intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT03212352.

Findings: Between June 28th 2018 and January 8th 2020, 175 women were randomised to mifepristone and 176 to placebo, including 344 in the intention-to-treat analysis. In the mifepristone group 136 (79•1%) of 172 participants reached complete evacuation compared to 101 (58•7%) of 172 participants in the placebo group (<0•0001, RR 1•35, 95% CI 1•16-1•56). Incidence of serious adverse events was significantly lower in the mifepristone group with 24 (14%) patients affected versus 55 (32%) in the placebo group ( = 0•0005) (Table 3).

Interpretation: Pre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL.

Funding: Healthcare Insurers Innovation Foundation, Radboud University Medical Centre, Canisius Wilhelmina Hospital.
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http://dx.doi.org/10.1016/j.eclinm.2020.100716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910666PMC
February 2021

Pre-Hospital Antiplatelet Therapy for STEMI Patients Undergoing Primary Percutaneous Coronary Intervention: What We Know and What Lies Ahead.

Thromb Haemost 2021 Mar 7. Epub 2021 Mar 7.

Maastricht University Medical Centre+, Gastroenterology & Hepatology, Maastricht, Netherlands.

Early recanalization of the infarct-related artery to achieve myocardial reperfusion is the primary therapeutic goal in patients with ST-elevation myocardial infarction (STEMI). In order to decrease the duration of ischemia, continuous efforts have been made to improve pre-hospital treatment and to target the early period after symptom onset, when the platelet content of the fresh coronary thrombus is maximal and the thrombi are dynamic, and thus more susceptible to powerful antiplatelet agents. There have been substantial advances in antiplatelet therapy in the last three decades with several classes of oral and intravenous antiplatelet agents with different therapeutic targets, pharmacokinetics, and pharmacodynamic properties. New parenteral drugs achieve immediate inhibition of platelet aggregation and fast and easy methods of administration may create the opportunity to bridge the initial gap in platelet inhibition observed with oral P2Y12 inhibitors. Moreover, potential future management of STEMI could directly involve select patients in the process with self-administered antiplatelet agents designed to achieve rapid reperfusion. However the potential anti-ischemic benefits of potent antiplatelet agents will need to be balanced against their risk of increased bleeding. This manuscript presents a comprehensive and updated review of pre-hospital antiplatelet therapy among STEMI patients undergoing primary percutaneous intervention and explores new therapies under development.
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http://dx.doi.org/10.1055/a-1414-5009DOI Listing
March 2021

High CD8+ tumour infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neo-adjuvant chemoradiotherapy.

Histopathology 2021 Mar 4. Epub 2021 Mar 4.

Pathology, Amsterdam, the Netherlands.

Introductions: Determining prognosis following poor response to neo-adjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastro-intestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT.

Methods: The prognostic significance of OAC-associated CD3+, CD4+, CD8+, FOXP3+ and PDL1 expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion.

Results: Tumour cell percentage positively correlated to immune infiltration markers. In good responders and moderate responders, none of the immune infiltrate parameters was associated with survival, in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (p=0.03) and high CD8+ infiltration was associated with worse OS (15 months vs 32 months, p=0.042).

Conclusion: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.
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http://dx.doi.org/10.1111/his.14361DOI Listing
March 2021

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

Lupus 2021 Apr 3;30(5):818-827. Epub 2021 Mar 3.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centers (Amsterdam UMC), University of Amsterdam, Amsterdam, the Netherlands.

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients.

Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases.

Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001).

Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.
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http://dx.doi.org/10.1177/0961203321998750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020305PMC
April 2021

Alcohol dose in septal ablation for hypertrophic obstructive cardiomyopathy.

Int J Cardiol 2021 Feb 27. Epub 2021 Feb 27.

Unit for Inherited Cardiac Diseases, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: The aim of this study was to evaluate short- and long-term outcomes related to dose of alcohol administered during alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy (HOCM). Current guidelines recommend using 1-3 mL of alcohol administered in the target septal perforator artery, but this recommendation is based more on practical experience of interventionalists rather than on systematic evidence.

Methods: We included 1448 patients and used propensity score to match patients who received a low-dose (1.0-1.9 mL) versus a high-dose (2.0-3.8 mL) of alcohol during ASA.

Results: The matched cohort analysis comprised 770 patients (n = 385 in both groups). There was a similar occurrence of 30-day post-procedural adverse events (13% vs. 12%; p = 0.59), and similar all-cause mortality rates (0.8% vs. 0.5%; p = 1) in the low-dose group and the high-dose group, respectively. In the long-term follow-up (5.4 ± 4.5 years), a total of 110 (14%) patients died representing 2.58 deaths and 2.64 deaths per 100 patient-years in the low dose and the high dose group (logrank, p = 0.92), respectively. There were no significant differences in the long-term dyspnea and left ventricular outflow gradient between the two groups. Patients treated with a low-dose of alcohol underwent more subsequent septal reduction procedures (logrank, p = 0.04).

Conclusions: Matched HOCM patients undergoing ASA with a low-dose (1.0-1.9 mL) or a high-dose (2.0-3.8 mL) of alcohol had similar short- and long-term outcomes. A higher rate of repeated septal reduction procedures was observed in the group treated with a low-dose of alcohol.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.056DOI Listing
February 2021

The Crossed Legs, "Ballerina" (or "Johnnie Walker") Configuration: A Solution or Bottle Neck in Endovascular Aneurysm Repair?

Eur J Vasc Endovasc Surg 2021 Apr 26;61(4):589-590. Epub 2021 Feb 26.

Centro Vascolare Ticino, Ospedale Regionale di Lugano, sede Civico, Lugano, Switzerland; Universitätsinstitut für Diagnostische, Interventionelle und Pädiatrische Radiologie, Inselspital, Universitätsspital Bern, Bern, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.ejvs.2021.01.041DOI Listing
April 2021

An apathetic child with hallucinations.

Tidsskr Nor Laegeforen 2021 Feb 22;141(3). Epub 2021 Feb 22.

Background: Lysergic acid diethylamide (LSD) is a potent, hallucinogenic substance that distorts the perception, state of consciousness and behaviour of the user. LSD poisonings are rare in children and may be difficult to recognise based on clinical symptoms alone.

Case Presentation: A young boy was admitted to the hospital because of bizarre behaviour and reduced responsiveness towards his parents. At first, he was agitated. Later he fell silent and became apathetic. He suffered from ataxia and showed signs of visual hallucinations. A conclusive diagnosis of LSD poisoning was made possible through targeted and specific laboratory testing of blood and urine samples. The patient recovered completely without any specific treatment.

Interpretation: We urge doctors who examine paediatric patients with acute and unexplained neuropsychiatric symptoms or abnormal behaviour to consider drug intoxication as a possible differential diagnosis. Blood and urine samples from such patients should be obtained as soon as possible and analysed for a broad spectrum of substances. No antidote exists for LSD. If sedation is required due to convulsions, tachycardia, agitation, or frightening hallucinations, treatment with a benzodiazepine, such as diazepam or midazolam, is recommended.
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http://dx.doi.org/10.4045/tidsskr.20.0569DOI Listing
February 2021

Electrochemical profiling and liquid chromatography-mass spectrometry characterization of synthetic cathinones: From methodology to detection in forensic samples.

Drug Test Anal 2021 Feb 24. Epub 2021 Feb 24.

AXES Research Group, Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium.

The emergence of new psychoactive drugs in the market demands rapid and accurate tools for the on-site classification of illegal and legal compounds with similar structures. Herein, a novel method for the classification of synthetic cathinones (SCs) is presented based on their electrochemical profile. First, the electrochemical profile of five common SC (i.e., mephedrone, ethcathinone, methylone, butylone, and 4-chloro-alpha-pyrrolidinovalerophenone) is collected to build calibration curves using square wave voltammetry on graphite screen-printed electrodes (SPEs). Second, the elucidation of the oxidation pathways, obtained by liquid chromatography-high-resolution mass spectrometry, allows the pairing of the oxidation products to the SC electrochemical profile, providing a selective and robust classification. Additionally, the effect of common adulterants and illicit drugs on the electrochemical profile of the SC is explored. Interestingly, a cathodic pretreatment of the SPE allows the selective detection of each SC in presence of electroactive adulterants. Finally, the electrochemical approach is validated with gas chromatography-mass spectrometry by analyzing 26 confiscated samples from seizures and illegal webshops. Overall, the electrochemical method exhibits a successful classification of SC including structural derivatives, a crucial attribute in an ever-diversifying drug market.
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http://dx.doi.org/10.1002/dta.3018DOI Listing
February 2021

Correction to: Impact of Enhanced Recovery After Surgery on Postoperative Outcomes for Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2021 Feb 19. Epub 2021 Feb 19.

Department of General Surgery, Division of Surgical Oncology, The University of Illinois at Chicago, 840 South Wood Street, M/C 820, Chicago, IL, 60612, USA.

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http://dx.doi.org/10.1245/s10434-021-09737-xDOI Listing
February 2021

Phenotypic characterization of PIGN-associated paroxysmal dyskinesia in Soft-coated wheaten terriers and preliminary response to acetazolamide therapy.

Vet J 2021 Mar 6;269:105606. Epub 2021 Jan 6.

Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, USA.

A hereditary movement disorder in Soft coated wheaten terriers (SCWT) has been associated with a mutation in PIGN which encodes an enzyme involved in synthesis of glycosylphosphatidylinositol (GPI). The objective of this study was to describe and classify the clinical phenotype and assess therapeutic response. Twenty-five SCWT and related dogs homozygous for PIGN:c.398C>T with paroxysmal dyskinesia were available for inclusion. Medical records and video recordings of 17 dogs were evaluated in a retrospective case series. Affected dogs had episodes of involuntary, hyperkinetic movements and dystonia. Median age of onset was 2.5 years. A typical episode consisted of rapid, irregular hyperflexion and extension of the pelvic limbs with some degree of truncal dystonia. A mild episode consisted of spontaneous flexion of one pelvic limb while walking which could resemble a lameness. Episodes lasted several minutes to several hours and occurred up to 10 times/day or more. They were not associated with exercise or fasting but were sometimes triggered by excitement or stress. Acetazolamide therapy improved nine of 11 dogs, in seven cases abolishing episodes. Five of 17 dogs treated with other agents had mild improvement with clonazepam (n = 2), levetiracetam (n = 1), or phenobarbital (n = 2). Paroxysmal dyskinesias must be differentiated from seizure disorders since they often respond to different therapies. The SCWT phenotype consisted predominantly of hyperkinesia, and can respond dramatically to acetazolamide. GPI anchors proteins to the cell surface including carbonic anhydrase IV which modulates synaptic pH in the brain. Altered activity of this enzyme may be the target of acetazolamide therapy.
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http://dx.doi.org/10.1016/j.tvjl.2021.105606DOI Listing
March 2021

The Total Thrombus Formation (T-TAS) platelet (PL) assay, a novel test that evaluates whole blood platelet thrombus formation under physiological conditions.

Platelets 2021 Feb 7:1-5. Epub 2021 Feb 7.

Department of Cardiology, St. Antonius Hospital , Nieuwegein, Netherlands.

Dual antiplatelet therapy (DAPT, aspirin, and a P2Y inhibitor) reduces thrombotic events in patients with coronary artery disease (CAD). The T-TAS PL assay uses arterial shear flow over collagen surface, better mimicking in vivo conditions compared to conventional agonist-based platelet function assays, to evaluate platelet function. Here, the platelet function in patients taking DAPT is evaluated with the T-TAS PL assay. In 57 patients with CAD, taking DAPT ≥7 days (n = 22 for clopidogrel, n = 15 for prasugrel, n = 20 for ticagrelor), T-TAS PL assessments were performed in duplicate, and expressed as area under the flow pressure curve within a 10-minute period (AUC10). The duplicate measurements were strongly correlated (r = 0.90, < .001), with an intra-assay coefficient of variation (CV) of 11,5%. For clopidogrel, the median AUC10 was 11.5 (IQR5.9-41.8), for prasugrel 28.8 (IQR10.3-37.6), and for ticagrelor 8.9 (IQR 6.4-10.9). All measurements were below the AUC10 cutoff of 260 measured in healthy volunteers, suggesting excellent discrimination of DAPT-treated and untreated persons. The new T-TAS PL assay demonstrated complete discrimination of platelet function in patients on DAPT based on an established cutoff. Ticagrelor showed lower levels of platelet function and a more uniform response compared to prasugrel and clopidogrel.
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http://dx.doi.org/10.1080/09537104.2021.1882669DOI Listing
February 2021