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Article ; Online: Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates.

Slingsby, Martina H Lundberg / Vijey, Prakrith / Tsai, I-Ting / Roweth, Harvey / Couldwell, Genevieve / Wilkie, Adrian R / Gaus, Hans / Goolsby, Jazana M / Okazaki, Ross / Terkovich, Brooke E / Semple, John W / Thon, Jonathan N / Henry, Scott P / Narayanan, Padmakumar / Italiano, Joseph E

Haematologica

2022 Volume 107, Issue 2, Page(s) 519–531

Abstract: Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O ...

Abstract	Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- and sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This article focuses on the underlying cause of the more common phenotype 1, investigating the effects of ASO on platelet production and platelet function. Five phosphorothioate ASO were studied: three 2'MOE sequences; 487660 (no effects on platelet count), 104838 (associated with phenotype 1), and 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets). Human cord bloodderived megakaryocytes were treated with these ASO to study their effects on proplatelet production. Platelet activation (determined by surface Pselectin) and platelet-leukocyte aggregates were analyzed in ASO-treated blood from healthy human volunteers. None of the ASO inhibited proplatelet production by human megakaryocytes. All the ASO were shown to bind to the platelet receptor glycoprotein VI (KD ~0.2-1.5 mM). CpG ASO had the highest affinity to glycoprotein VI, the most potent platelet-activating effects and led to the greatest formation of platelet-leukocyte aggregates. 2'MOE ASO 487660 had no detectable platelet effects, while 2'MOE ASOs 104838 and 501861 triggered moderate platelet activation and SYKdependent formation of platelet-leukocyte aggregates. Donors with higher platelet glycoprotein VI levels had greater ASO-induced platelet activation. Sequence-dependent ASO-induced platelet activation and platelet-leukocyte aggregates may explain phenotype 1 (moderate drops in platelet count). Platelet glycoprotein VI levels could be useful as a screening tool to identify patients at higher risk of ASO-induced platelet side effects.
MeSH term(s)	Blood Platelets ; Humans ; Leukocytes ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Platelet Activation ; Platelet Count
Chemical Substances	Oligonucleotides, Antisense
Language	English
Publishing date	2022-02-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.260059
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Article ; Online: Dopamine D3 receptor Ser9Gly and catechol-o-methyltransferase Val158Met polymorphisms and acute pain in sickle cell disease.

Jhun, Ellie / He, Ying / Yao, Yingwei / Molokie, Robert E / Wilkie, Diana J / Wang, Zaijie Jim

Anesthesia and analgesia

2014 Volume 119, Issue 5, Page(s) 1201–1207

Abstract: ... from a sickle cell pain crisis. We performed genotyping for catechol-O-methyltransferase (COMT) Val158Met ...

Abstract	Background: Pain in sickle cell disease (SCD) is characterized by episodes of acute pain, primarily responsible for acute health care utilization, and persistent chronic pain. Pain severity and frequency vary significantly among patients with SCD. In this study, we investigated the possible contribution of monoamine gene polymorphisms to pain variation. Methods: Adult subjects with SCD completed PAINReportIt, a computerized McGill Pain Questionnaire, from which we calculated the Composite Pain Index. Utilization data were obtained from the medical record and biweekly telephone calls for 12 months. Utilization is defined as admissions to the emergency department and/or the acute care center resulting from a sickle cell pain crisis. We performed genotyping for catechol-O-methyltransferase (COMT) Val158Met (rs4680) and dopamine D3 receptor (DRD3) Ser9Gly (rs6280) polymorphisms, which were analyzed for associations with pain phenotypes. Results: Binary logistic models revealed that DRD3 Ser9Gly heterozygote patients were more likely not to have an acute pain crisis (odds ratio [OR] [95% confidence interval {CI}], 4.37 [1.39-22.89]; P = 0.020), which remained so when demographic variables were considered (OR [95% CI], 4.53 [1.41-28.58]; P = 0.016). COMT Val158Met Met allele showed lower probability for zero utilization (OR [95% CI], 0.32 [0.12-0.83]; P = 0.020) than the Val allele. In the negative binomial regression analysis, subjects with COMT Met/Met genotype had utilization incident rate ratio (95% CI) of 2.20 (1.21-3.99) over those with Val/Val (P = 0.010). Conclusions: These exploratory findings suggest that DRD3 Ser9Gly and COMT Val158Met may contribute to pain heterogeneity in SCD, as suggested by the different rates of acute pain crisis. Specifically, SCD patients with the DRD3 homozygote genotypes, COMT 158 Met allele or Met/Met genotype, are more likely to have acute care utilization, an indicator of acute pain. These results, however, will need to be further examined in future large prospective studies.
MeSH term(s)	Acute Pain/etiology ; Acute Pain/genetics ; Adult ; Alleles ; Anemia, Sickle Cell/complications ; Anemia, Sickle Cell/genetics ; Catechol O-Methyltransferase/genetics ; DNA/genetics ; Female ; Genotype ; Humans ; Male ; Pain Measurement ; Polymorphism, Genetic/genetics ; Polymorphism, Single Nucleotide ; Receptors, Dopamine D3/genetics
Chemical Substances	Receptors, Dopamine D3 ; DNA (9007-49-2) ; Catechol O-Methyltransferase (EC 2.1.1.6)
Language	English
Publishing date	2014-08-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000000382
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Article ; Online: The clinical characteristics, managements, and outcomes of acute myocardial infarction in osteoarthritis patients; a cross-sectional analysis of 6.5 million patients.

Parmar, Simran Singh / Mohamed, Mohamed O / Mamas, Mamas A / Wilkie, Ross

Expert review of cardiovascular therapy

2024 Volume 22, Issue 1-3, Page(s) 121–129

Abstract: Objectives: The prevalence of osteoarthritis (OA) and cardiovascular disease are increasing and both conditions share similar risk factors. We investigated the association between OA and receipt of invasive managements and clinical outcomes in patients ... ...

Abstract	Objectives: The prevalence of osteoarthritis (OA) and cardiovascular disease are increasing and both conditions share similar risk factors. We investigated the association between OA and receipt of invasive managements and clinical outcomes in patients with acute myocardial infarction (AMI). Methods: Using the National Inpatient Sample, adjusted binary logistic regression determined the association between OA and each outcome variable. Results: Of 6,561,940 AMI hospitalizations, 6.3% had OA. OA patients were older and more likely to be female. OA was associated with a decreased odds of coronary angiography (adjusted odds ratio 0.91; 95% confidence interval 0.90, 0.92), PCI (0.87; 0.87, 0.88), and coronary artery bypass grafting (0.98; 0.97, 1.00). OA was associated with a decreased odds of adverse outcomes (in-hospital mortality: 0.68; 0.67, 0.69; major acute cardiovascular and cerebrovascular events: 0.71; 0.70, 0.72; all-cause bleeding: 0.76; 0.74, 0.77; and stroke/TIA: 0.84; 0.82, 0.87). Conclusions: This study of a representative sample of the US population highlights that OA patients are less likely to be offered invasive interventions following AMI. OA was also associated with better outcomes post-AMI, possibly attributed to a misclassification bias where unwell patients with OA were less likely to receive an OA code because codes for serious illness took precedence.
MeSH term(s)	Humans ; Female ; Male ; Cross-Sectional Studies ; Percutaneous Coronary Intervention/adverse effects ; Myocardial Infarction/etiology ; Coronary Artery Bypass ; Risk Factors ; Osteoarthritis/etiology ; Hospital Mortality ; Treatment Outcome
Language	English
Publishing date	2024-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2192343-7
ISSN	1744-8344 ; 1477-9072
ISSN (online)	1744-8344
ISSN	1477-9072
DOI	10.1080/14779072.2024.2311696
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Article ; Online: Mendelian inheritance revisited: dominance and recessiveness in medical genetics.

Zschocke, Johannes / Byers, Peter H / Wilkie, Andrew O M

Nature reviews. Genetics

2023 Volume 24, Issue 7, Page(s) 442–463

Abstract: Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these ... ...

Abstract	Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.
MeSH term(s)	Genetics, Medical ; Genotype ; Phenotype ; Mutation ; Alleles
Language	English
Publishing date	2023-02-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2035157-4
ISSN	1471-0064 ; 1471-0056
ISSN (online)	1471-0064
ISSN	1471-0056
DOI	10.1038/s41576-023-00574-0
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Article ; Online: Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients.

Edwards, Olivia / Burris, Alicia / Lua, Josh / Wilkie, Diana J / Ezenwa, Miriam O / Doré, Sylvain

Genes

2022 Volume 13, Issue 1

Abstract: This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and ...

Abstract	This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.
MeSH term(s)	Anemia, Sickle Cell/complications ; Anemia, Sickle Cell/genetics ; Animals ; Haptoglobins/genetics ; Humans ; Oxidative Stress ; Polymorphism, Genetic ; Stroke/etiology ; Stroke/genetics ; Stroke/pathology
Chemical Substances	Haptoglobins
Language	English
Publishing date	2022-01-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13010144
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Article ; Online: Adherence to a reproductive health intervention for young adults with sickle cell.

Eades-Brown, Nyema T / Oguntoye, Anne O / Aldossary, Dalal / Ezenwa, Miriam O / Duckworth, Laurie / Dede, Duane / Johnson-Mallard, Versie / Yao, Yingwei / Gallo, Agatha / Wilkie, Diana J

Journal of the American Association of Nurse Practitioners

2024

Abstract: Background: The CHOICES intervention is tailored specifically for young adults with sickle cell disease (SCD) or sickle cell trait (SCT). The face-to-face (F2F) delivery format is feasible with efficacy for improving knowledge about reproductive health ... ...

Abstract	Background: The CHOICES intervention is tailored specifically for young adults with sickle cell disease (SCD) or sickle cell trait (SCT). The face-to-face (F2F) delivery format is feasible with efficacy for improving knowledge about reproductive health for those with SCD or SCT. Purpose: The purpose of the study was to compare the participant adherence to a remote online CHOICES intervention study (N = 107) and a F2F CHOICES intervention study (N = 234). Methodology: In both studies, participants with SCD or SCT were randomized into experimental or usual care control groups. Descriptive statistics were collected for all participants by group in both studies. Adherence was measured by retention at each data collection time point. Independent t-tests were conducted to compare mean participant adherence of the F2F and online studies postbaseline (6, 12, 18, and 24 months). Results: There was a significant difference in mean adherence postbaseline between the studies (p = .005). The results suggest that more research is necessary for proper online participant retention. Conclusion: Advance practice nurses that are well informed on CHOICES can transmit the availability of this evidence-based intervention to this special population. Special referral for the CHOICES intervention, which is tailored specifically for young adults with SCD or SCT, may increase adherence to the intervention if it comes from trusted health care providers. Implications: Nurse practitioners are educators in primary and acute care settings. Encounters with reproductive age populations with SCD or SCT can occur in both settings.
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2716317-9
ISSN	2327-6924 ; 1745-7599 ; 2327-6886 ; 1041-2972
ISSN (online)	2327-6924 ; 1745-7599
ISSN	2327-6886 ; 1041-2972
DOI	10.1097/JXX.0000000000000997
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Article ; Online: Gregor Mendel and the concepts of dominance and recessiveness.

Zschocke, Johannes / Byers, Peter H / Wilkie, Andrew O M

Nature reviews. Genetics

2022 Volume 23, Issue 7, Page(s) 387–388

Language	English
Publishing date	2022-05-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2035157-4
ISSN	1471-0064 ; 1471-0056
ISSN (online)	1471-0064
ISSN	1471-0056
DOI	10.1038/s41576-022-00495-4
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Article ; Online: Development and validation of an electrocardiographic artificial intelligence model for detection of peripartum cardiomyopathy.

Karabayir, Ibrahim / Wilkie, Gianna / Celik, Turgay / Butler, Liam / Chinthala, Lokesh / Ivanov, Alexander / Moore Simas, Tiffany A / Davis, Robert L / Akbilgic, Oguz

American journal of obstetrics & gynecology MFM

2024 Volume 6, Issue 4, Page(s) 101337

Abstract: Background: This study used electrocardiogram data in conjunction with artificial intelligence methods as a noninvasive tool for detecting peripartum cardiomyopathy.: Objective: This study aimed to assess the efficacy of an artificial intelligence- ... ...

Abstract	Background: This study used electrocardiogram data in conjunction with artificial intelligence methods as a noninvasive tool for detecting peripartum cardiomyopathy. Objective: This study aimed to assess the efficacy of an artificial intelligence-based heart failure detection model for peripartum cardiomyopathy detection. Study design: We first built a deep-learning model for heart failure detection using retrospective data at the University of Tennessee Health Science Center. Cases were adult and nonpregnant female patients with a heart failure diagnosis; controls were adult nonpregnant female patients without heart failure. The model was then tested on an independent cohort of pregnant women at the University of Tennessee Health Science Center with or without peripartum cardiomyopathy. We also tested the model in an external cohort of pregnant women at Atrium Health Wake Forest Baptist. Key outcomes were assessed using the area under the receiver operating characteristic curve. We also repeated our analysis using only lead I electrocardiogram as an input to assess the feasibility of remote monitoring via wearables that can capture single-lead electrocardiogram data. Results: The University of Tennessee Health Science Center heart failure cohort comprised 346,339 electrocardiograms from 142,601 patients. In this cohort, 60% of participants were Black and 37% were White, with an average age (standard deviation) of 53 (19) years. The heart failure detection model achieved an area under the curve of 0.92 on the holdout set. We then tested the ability of the heart failure model to detect peripartum cardiomyopathy in an independent University of Tennessee Health Science Center cohort of pregnant women and an external Atrium Health Wake Forest Baptist cohort of pregnant women. The independent University of Tennessee Health Science Center cohort included 158 electrocardiograms from 115 patients; our deep-learning model achieved an area under the curve of 0.83 (0.77-0.89) for this data set. The external Atrium Health Wake Forest Baptist cohort involved 80 electrocardiograms from 43 patients; our deep-learning model achieved an area under the curve of 0.94 (0.91-0.98) for this data set. For identifying peripartum cardiomyopathy diagnosed ≥10 days after delivery, the model achieved an area under the curve of 0.88 (0.81-0.94) for the University of Tennessee Health Science Center cohort and of 0.96 (0.93-0.99) for the Atrium Health Wake Forest Baptist cohort. When we repeated our analysis by building a heart failure detection model using only lead-I electrocardiograms, we obtained similarly high detection accuracies, with areas under the curve of 0.73 and 0.93 for the University of Tennessee Health Science Center and Atrium Health Wake Forest Baptist cohorts, respectively. Conclusion: Artificial intelligence can accurately detect peripartum cardiomyopathy from electrocardiograms alone. A simple electrocardiographic artificial intelligence-based peripartum screening could result in a timelier diagnosis. Given that results with 1-lead electrocardiogram data were similar to those obtained using all 12 leads, future studies will focus on remote screening for peripartum cardiomyopathy using smartwatches that can capture single-lead electrocardiogram data.
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Journal Article
ISSN	2589-9333
ISSN (online)	2589-9333
DOI	10.1016/j.ajogmf.2024.101337
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Article ; Online: Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene.

Care, Helen / Luscombe, Carrie / Wall, Steven A / Dalton, Louise / Johnson, David / Wilkie, Andrew O M

The Journal of craniofacial surgery

2022 Volume 33, Issue 6, Page(s) 1847–1852

Abstract: Abstract: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 ...

Abstract	Abstract: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF- related craniosynostosis, together with three of their carrier parents.There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity.It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties.The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF -related mutation.
MeSH term(s)	Behavior ; Child ; Cognition ; Communication Disorders ; Craniosynostoses/genetics ; Humans ; Language ; Repressor Proteins/genetics ; Speech ; Speech Disorders/genetics
Chemical Substances	ERF protein, human ; Repressor Proteins
Language	English
Publishing date	2022-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1159501-2
ISSN	1536-3732 ; 1049-2275
ISSN (online)	1536-3732
ISSN	1049-2275
DOI	10.1097/SCS.0000000000008659
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Article ; Online: Gonadal mosaicism and non-invasive prenatal diagnosis for 'reassurance' in sporadic paternal age effect (PAE) disorders.

Wilkie, Andrew O M / Goriely, Anne

Prenatal diagnosis

2017 Volume 37, Issue 9, Page(s) 946–948

MeSH term(s)	Female ; Humans ; Mosaicism ; Paternal Age ; Pedigree ; Pregnancy ; Prenatal Diagnosis
Language	English
Publishing date	2017-08-01
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	82031-3
ISSN	1097-0223 ; 0197-3851
ISSN (online)	1097-0223
ISSN	0197-3851
DOI	10.1002/pd.5108
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