Publications by authors named "Christopher Barnett"

120 Publications

Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia.

BMC Med Genomics 2021 Feb 27;14(1):64. Epub 2021 Feb 27.

Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, North Adelaide, SA, Australia.

Background: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH.

Case Presentation: We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus.

Conclusion: We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.
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http://dx.doi.org/10.1186/s12920-021-00911-4DOI Listing
February 2021

In-depth analysis of a case of persistent severe chronic thromboembolic pulmonary hypertension.

Cardiovasc Revasc Med 2020 Jul 10. Epub 2020 Jul 10.

MedStar Washington Hospital Center, Department of Cardiology, United States of America.

Pulmonary hypertension (PH) is a disease characterized by an increase in the pulmonary vascular resistance that typically progresses to right heart failure and death. It is classified into five groups. Management depends on the group classification. Group four PH, chronic thromboembolic pulmonary hypertension (CTEPH) is thought to be a result of acute pulmonary emboli that cause fibrosis and scarring of the pulmonary arteries with consequent obstruction. The diagnosis of CTEPH is made by identifying perfusion abnormalities on ventilation/perfusion (V/Q) scan. Other studies required for the diagnostic evaluation include transthoracic echocardiogram (TTE), right heart catheterization (RHC), NT pro-B-type natriuretic peptide (NT Pro-BNP) and thrombophilia evaluation. Several other tests needed to exclude other causes of pulmonary hypertension include high resolution computed tomography (HRCT), connective tissue disease evaluation, thyroid function testing, human immunodeficiency virus testing and liver ultrasonography to exclude portal hypertension. The treatment for CTEPH is surgical pulmonary endarterectomy (PEA). In patients who are not candidates or decline PEA, pulmonary balloon angioplasty (BPA) may be useful, however, further studies are required. Several pulmonary artery hypertension (PAH) medications have been studied in the management of inoperable CTEPH or persistent PH following PEA including Bosentan (improves hemodynamics but not exercise capacity), Macitentan (improves both hemodynamics and clinical parameters) and Riociguat (improves both hemodynamics and exercise capacity). However only Riociguat is approved by the food and drug association for this indication.
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http://dx.doi.org/10.1016/j.carrev.2020.07.012DOI Listing
July 2020

New pathogenic mutations associated with DGAT1 deficiency.

J Pediatr 2021 Feb 16. Epub 2021 Feb 16.

Department of Gastroenterology, Women's & Children's Hospital, South Australia; School of Paediatrics, University of Adelaide, South Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.02.028DOI Listing
February 2021

Learning from scaling up ultra-rapid genomic testing for critically ill children to a national level.

NPJ Genom Med 2021 Jan 28;6(1). Epub 2021 Jan 28.

Australian Genomics, Melbourne, VIC, Australia.

In scaling up an ultra-rapid genomics program, we used implementation science principles to design and investigate influences on implementation and identify strategies required for sustainable "real-world" services. Interviews with key professionals revealed the importance of networks and relationship building, leadership, culture, and the relative advantage afforded by ultra-rapid genomics in the care of critically ill children. Although clinical geneticists focused on intervention characteristics and the fit with patient-centered care, intensivists emphasized the importance of access to knowledge, in particular from clinical geneticists. The relative advantage of ultra-rapid genomics and trust in consistent and transparent delivery were significant in creating engagement at initial implementation, with appropriate resourcing highlighted as important for longer term sustainability of implementation. Our findings demonstrate where common approaches can be used and, significantly, where there is a need to tailor support by professional role and implementation phase, to maximize the potential of ultra-rapid genomic testing to improve patient care.
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http://dx.doi.org/10.1038/s41525-020-00168-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843635PMC
January 2021

Intuitive, reproducible high-throughput molecular dynamics in Galaxy: a tutorial.

J Cheminform 2020 Sep 10;12(1):54. Epub 2020 Sep 10.

Department of Computer Science, University of Freiburg, Georges-Köhler-Allee 106, Freiburg, Germany.

This paper is a tutorial developed for the data analysis platform Galaxy. The purpose of Galaxy is to make high-throughput computational data analysis, such as molecular dynamics, a structured, reproducible and transparent process. In this tutorial we focus on 3 questions: How are protein-ligand systems parameterized for molecular dynamics simulation? What kind of analysis can be carried out on molecular trajectories? How can high-throughput MD be used to study multiple ligands? After finishing you will have learned about force-fields and MD parameterization, how to conduct MD simulation and analysis for a protein-ligand system, and understand how different molecular interactions contribute to the binding affinity of ligands to the Hsp90 protein.
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http://dx.doi.org/10.1186/s13321-020-00451-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488338PMC
September 2020

The Garlic Compound Z-Ajoene, S-Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages.

Mol Nutr Food Res 2021 02 18;65(3):e2000854. Epub 2020 Dec 18.

Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, 7600, South Africa.

Scope: Garlic (Allium sativum) has been used for centuries as a prophylactic and therapeutic medicinal agent to control inflammation-associated pathologies. To investigate the underlying mechanisms, an in vitro inflammatory model is established using RAW264.7 murine macrophages exposed to low-doses of lipopolysaccharide (LPS) in the presence of garlic compounds allicin and Z-ajoene (ZA), mimicking regular garlic consumption.

Methods And Results: Both allicin and Z-ajoene dampen both transcript and protein expression of the pro-inflammatory cytokines IL1β, IL6, and IL12β, and upregulate the expression of the anti-inflammatory cytokine IL10. Protein arrays of selected secreted inflammatory mediators confirm that Z-ajoene has a pronounced down-regulatory effect on LPS-induced inflammatory cytokines and chemokines. Many of these proteins are known targets of the transcription factor signal transducer and activator of transcription 3 (STAT3); and indeed, Z-ajoene or its analogue dansyl-ajoene is found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S-thiolation at Cys108, Cys367, and Cys687. Z-Ajoene dose-dependently and non-competitively inhibit the activity of cyclooxygenase 2 (COX2), possibly attributed to S-thiolation at Cys9 and Cys299.

Conclusion: The characterization of Z-ajoene's activity of targeting and covalently modifying STAT3 and COX2, both important regulators of inflammation, may contribute to the health benefits of regular dietary garlic consumption.
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http://dx.doi.org/10.1002/mnfr.202000854DOI Listing
February 2021

Gene-specific facial dysmorphism in Axenfeld-Rieger syndrome caused by FOXC1 and PITX2 variants.

Am J Med Genet A 2021 02 24;185(2):434-439. Epub 2020 Nov 24.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.
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http://dx.doi.org/10.1002/ajmg.a.61982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839469PMC
February 2021

Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen-antibody binding.

Beilstein J Org Chem 2020 13;16:2540-2550. Epub 2020 Oct 13.

Scientific Computing Research Unit and Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.

When faced with the investigation of the preferential binding of a series of ligands against a known target, the solution is not always evident from single structure analysis. An ensemble of structures generated from computer simulations is valuable; however, visual analysis of the extensive structural data can be overwhelming. Rapid analysis of trajectory data, with tools available in the Galaxy platform, can be used to understand key features and compare differences that inform the preferential ligand structure that favors binding. We illustrate this informatics approach by investigating the in-silico binding of a peptide and glycopeptide epitope of the glycoprotein Mucin 1 (MUC1) binding with the antibody AR20.5. To study the binding, we performed molecular dynamics simulations using OpenMM and then used the Galaxy platform for data analysis. The same analysis tools are applied to each of the simulation trajectories and this process was streamlined by using Galaxy workflows. The conformations of the antigens were analyzed using root-mean-square deviation, end-to-end distance, Ramachandran plots, and hydrogen bonding analysis. Additionally, RMSF and clustering analysis were carried out. These analyses were used to rapidly assess key features of the system, interrogate the dynamic structure of the ligand, and determine the role of glycosylation on the conformational equilibrium. The glycopeptide conformations in solution change relative to the peptide; thus a partially pre-structuring is seen prior to binding. Although the bound conformation of peptide and glycopeptide is similar, the glycopeptide fluctuates less and resides in specific conformers for more extended periods. This structural analysis which gives a high-level view of the features in the system under observation, could be readily applied to other binding problems as part of a general strategy in drug design or mechanistic analysis.
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http://dx.doi.org/10.3762/bjoc.16.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590620PMC
October 2020

Severe Cloverleaf Skull Deformity in c.1061C>G (p.Ser354Cys) Mutated Fibroblast Growth Factor Receptor 2 Gene in Crouzon Syndrome.

J Craniofac Surg 2021 Jan-Feb 01;32(1):261-264

Australian Craniofacial Unit.

Abstract: Cloverleaf skull deformity (CSD), or Kleeblattschädel, is a condition with severe and unpatterned multisuture craniosynostosis, resulting in a trilobar-shaped skull. This deformity mainly comprises a cranio-orbito-facial malformation that leads to a spectrum of multidisciplinary issues. Several syndromes are associated with CSD, such as Crouzon syndrome (CS). Here, we report the case of an infant with CS and the pathogenic c.1061C>G (p.Ser354Cys) variant of the fibroblast growth factor receptor 2 (FGFR2) gene. The child presented with the severe form of CSD despite having a normal, mid-trimester, sonographic scan.
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http://dx.doi.org/10.1097/SCS.0000000000006999DOI Listing
September 2020

BRIDGE: An Open Platform for Reproducible High-Throughput Free Energy Simulations.

J Chem Inf Model 2020 Nov 2;60(11):5290-5295. Epub 2020 Sep 2.

Scientific Computing Research Unit and Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.

Biomolecular Reaction and Interaction Dynamics Global Environment (BRIDGE) is an open-source web platform developed with the aim to provide an environment for the design of reliable methods to conduct reproducible biomolecular simulations. It is built on the well-known Galaxy bioinformatics platform. Through this, BRIDGE hosts computational chemistry tools on public web servers for internet use and provides machine- and operating-system-independent portability using the Docker container platform for local use. This construction improves the accessibility, shareability, and reproducibility of computational methods for molecular simulations. Here we present integrated free energy tools (or apps) to calculate absolute binding free energies (ABFEs) and relative binding free energies (RBFEs), as illustrated through use cases. We present free energy perturbation (FEP) methods contained in various software packages such as GROMACS and YANK that are independent of hardware configuration, software libraries, or operating systems when ported in the Galaxy-BRIDGE Docker container platform. By performing cyclin-dependent kinase 2 (CDK2) FEP calculations on geographically dispersed web servers (in Africa and Europe), we illustrate that large-scale computations can be performed using the exact same codes and methodology by collaborating groups through publicly shared protocols and workflows. The ease of public sharing and independent reproduction of simulations via BRIDGE makes possible an open review of methods and complete simulation protocols. This makes the discovery of inhibitors for drug targets accessible to nonexperts and the computer experiments that are used to arrive at leads verifiable by experts and reviewers. We illustrate this on β-galactoside α-2,3-sialyltransferase I (ST3Gal-I), a breast cancer drug target, where a combination of RBFE and ABFE methods are used to compute the binding free energies of three inhibitors.
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http://dx.doi.org/10.1021/acs.jcim.0c00206DOI Listing
November 2020

Parental experiences of ultrarapid genomic testing for their critically unwell infants and children.

Genet Med 2020 Dec 28;22(12):1976-1985. Epub 2020 Jul 28.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.

Purpose: To explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children.

Methods: Parents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome Scale.

Results: With 96 survey invitations sent, the response rate was 57% (n = 55). Most parents reported receiving enough information during pretest (n = 50, 94%) and post-test (n = 44, 83%) counseling. Perceptions varied regarding benefits of testing, however most parents reported no or mild decision regret (n = 45, 82%). The majority of parents (31/52, 60%) were extremely concerned about the condition recurring in future children, regardless of actual or perceived recurrence risk. Parents whose child received a diagnostic result reported higher empowerment.

Conclusion: This study provides valuable insight into parental experiences of ultrarapid genomic testing in critically unwell children, including decision regret, empowerment, and post-test reproductive planning, to inform design and delivery of rapid diagnosis programs. The findings suggest considerations for pre- and post-test counseling that may influence parental experiences during the testing process and beyond, such as the importance of realistically conveying the likelihood for clinical and/or personal utility.
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http://dx.doi.org/10.1038/s41436-020-0912-4DOI Listing
December 2020

Approach to Ventricular Arrhythmias in the Intensive Care Unit.

J Intensive Care Med 2020 Jul 24:885066620912701. Epub 2020 Jul 24.

Division of Cardiology, University of Alberta Hospital, Edmonton, Alberta, Canada.

Arrhythmias are commonly encountered in the intensive care unit as a primary admitting diagnosis or secondary to an acute illness. Appropriate identification and treatment of ventricular arrhythmias in this setting are particularly important to reduce morbidity and mortality. This review highlights the epidemiology, mechanisms, electrocardiographic features, and treatment of ventricular arrhythmias.
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http://dx.doi.org/10.1177/0885066620912701DOI Listing
July 2020

Quinoline-triazole half-sandwich iridium(III) complexes: synthesis, antiplasmodial activity and preliminary transfer hydrogenation studies.

Dalton Trans 2020 Aug;49(33):11543-11555

Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa.

Iridium(iii) half-sandwich complexes containing 7-chloroquinoline-1,2,3-triazole hybrid ligands were synthesised and their inhibitory activities evaluated against the Plasmodium falciparum malaria parasite. Supporting computational analysis revealed that metal coordination to the quinoline nitrogen occurs first, forming a kinetic product that, upon heating over time, forms a more stable cyclometallated thermodynamic product. Single crystal X-ray diffraction confirmed the proposed molecular structures of both isolated kinetic and thermodynamic products. Complexation with iridium significantly enhances the in vitro activity of selected ligands against the chloroquine-sensitive (NF54) Plasmodium falciparum strain, with selected complexes being over one hundred times more active than their respective ligands. No cross-resistance was observed in the chloroquine-resistant (K1) strain. No cytotoxicity was observed for selected complexes tested against the mammalian Chinese Hamster Ovarian (CHO) cell line. In addition, speed-of-action assays and β-haematin inhibition studies were performed. Through preliminary qualitative and quantitative cell-free experiments, it was found that the two most active neutral, cyclometallated complexes can act as transfer hydrogenation catalysts, by reducing β-nicotinamide adenine dinucleotide (NAD+) to NADH in the presence of a hydrogen source, sodium formate.
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http://dx.doi.org/10.1039/d0dt01935fDOI Listing
August 2020

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

JAMA 2020 06;323(24):2503-2511

Australian Genomics Health Alliance, Parkville, Australia.

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.

Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.

Design, Setting, And Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.

Exposures: Ultra-rapid exome sequencing.

Main Outcomes And Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.

Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).

Conclusions And Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.
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http://dx.doi.org/10.1001/jama.2020.7671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312414PMC
June 2020

Optimizing Computed Tomography for Detection of Pulmonary Thromboembolism in Patients With Fontan Circulation.

Cureus 2020 May 28;12(5):e8326. Epub 2020 May 28.

Cardiology, MedStar Washington Hospital Center, Washington, DC, USA.

Congenital heart disease (CHD) patients who have undergone the Fontan procedure or one of its variants usually have altered vascular anatomy. Consequently, this poses a challenge when diagnosing pulmonary thromboembolism (PTE) with computed tomography (CT). Detailed review of the type of surgery performed and the person's individual anatomy beforehand can help in choosing the appropriate diagnostic CT modality and technique. It would also help reduce false-positive and false-negative test results that would otherwise result in unnecessary anticoagulation, as well as avoid needless radiation exposure and additional cost, respectively.
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http://dx.doi.org/10.7759/cureus.8326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265774PMC
May 2020

Embolic ST-elevation Myocardial Infarction from Candida Endocarditis.

Cureus 2020 Apr 25;12(4):e7833. Epub 2020 Apr 25.

Cardiology, MedStar Washington Hospital Center, Washington, USA.

Infective endocarditis in intravenous drug users is uncommon in left-sided native valves. Adding to the rarity, in this case, is endocarditis from Candida species complicated by ST-elevation myocardial infarction. Embolic myocardial infarction has worse outcomes as compared to other etiologies, and the management of septic embolic myocardial infarction is rather challenging. The management of embolic myocardial infarction from Candida endocarditis vegetation includes antifungal therapy. The use of anti-thrombotic therapy and anticoagulation carries a significant risk of fatal neurologic complications and has been controversial, with limited observational data available. Among percutaneous coronary interventions, balloon angioplasty and stenting have been associated with multiple complications while aspiration embolectomy appears to be a safer option. Surgical management is considered if medical and interventional therapies fail or if there is an indication for valve replacement.
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http://dx.doi.org/10.7759/cureus.7833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250518PMC
April 2020

Novel de novo 2q14.3 deletion disrupting CNTNAP5 in a girl with intellectual impairment, thin corpus callosum, and microcephaly.

Am J Med Genet A 2020 07 24;182(7):1824-1828. Epub 2020 Apr 24.

Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, North Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1002/ajmg.a.61592DOI Listing
July 2020

Percutaneous transcatheter release of stuck mechanical mitral valve leaflet.

Eur Heart J 2020 Nov;41(41):4072

Section of Interventional Cardiology, MedStar Washington Hospital Center, 110 Irving St. NW, Suite 4B-1, Washington, DC 20010, USA.

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http://dx.doi.org/10.1093/eurheartj/ehaa228DOI Listing
November 2020

COVID-19 and Disruptive Modifications to Cardiac Critical Care Delivery: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 07 16;76(1):72-84. Epub 2020 Apr 16.

Department of Critical Care and Division of Cardiology, Department of Medicine, University of Alberta Hospital, Alberta, Canada. Electronic address: https://twitter.com/seanvandiepen.

The COVID-19 pandemic has presented a major unanticipated stress on the workforce, organizational structure, systems of care, and critical resource supplies. To ensure provider safety, to maximize efficiency, and to optimize patient outcomes, health systems need to be agile. Critical care cardiologists may be uniquely positioned to treat the numerous respiratory and cardiovascular complications of the SARS-CoV-2 and support clinicians without critical care training who may be suddenly asked to care for critically ill patients. This review draws upon the experiences of colleagues from heavily impacted regions of the United States and Europe, as well as lessons learned from military mass casualty medicine. This review offers pragmatic suggestions on how to implement scalable models for critical care delivery, cultivate educational tools for team training, and embrace technologies (e.g., telemedicine) to enable effective collaboration despite social distancing imperatives.
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http://dx.doi.org/10.1016/j.jacc.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161519PMC
July 2020

CDH1-related blepharocheilodontic syndrome is associated with diffuse gastric cancer risk.

Am J Med Genet A 2020 07 17;182(7):1780-1784. Epub 2020 Apr 17.

Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

We report the first case of diffuse gastric cancer in an individual with familial blepharocheilodontic syndrome (BCD) due to a germline CDH1 likely pathogenic variant. To date, other BCD affected relatives are nonpenetrant for diffuse gastric cancer posing challenges to counseling regarding gastric and breast cancer surveillance, and preventative total gastrectomy.
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http://dx.doi.org/10.1002/ajmg.a.61601DOI Listing
July 2020

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.

Am J Med Genet A 2020 05 6;182(5):1273-1277. Epub 2020 Mar 6.

Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.
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http://dx.doi.org/10.1002/ajmg.a.61541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217179PMC
May 2020

Plaque Rupture-Induced Myocardial Infarction and Mechanical Circulatory Support in Alpha-Gal Allergy.

Case Rep Cardiol 2020 17;2020:5282843. Epub 2020 Feb 17.

MedStar Washington Hospital Center, Washington, DC, USA.

Alpha-gal (AG) allergy is an IgE-mediated allergic reaction to galactose-alpha-1,3-galactose found in mammalian meat. Heparin, being derived from porcine intestinal tissue, may have a degree of cross-reactivity with AG antigen and thus place patients at risk for allergic and even anaphylactic reactions. This is especially important in patients with myocardial infarction (MI) and mechanical circulatory support, such as a left ventricular assist device (LVAD), since anticoagulation is immediately required. Therefore, individualized assessment and preoperative planning is needed regarding the use of heparin vs. nonheparinoid products in such a population.
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http://dx.doi.org/10.1155/2020/5282843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048905PMC
February 2020

ProtoCaller: Robust Automation of Binding Free Energy Calculations.

J Chem Inf Model 2020 04 26;60(4):1917-1921. Epub 2020 Mar 26.

School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom.

ProtoCaller is a Python library distributed through Anaconda which automates relative protein-ligand binding free energy calculations in GROMACS. It links a number of popular specialized tools used to perform protein setup and parametrization, such as PDB2PQR, Modeller, and AmberTools. ProtoCaller supports commonly used AMBER force fields with additional cofactor parameters, and AM1-BCC is used to derive ligand charges. ProtoCaller also comes with an extensive PDB parser, an enhanced maximum common substructure algorithm providing improved ligand-ligand mapping, and a light GROMACS wrapper for running multiple molecular dynamics simulations. ProtoCaller is highly relevant to most researchers in the field of biomolecular simulation, allowing a customizable balance between automation and user intervention.
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http://dx.doi.org/10.1021/acs.jcim.9b01158DOI Listing
April 2020

Incidence, underlying conditions, and outcomes of patients receiving acute renal replacement therapies in tertiary cardiac intensive care units: An analysis from the Critical Care Cardiology Trials Network Registry.

Am Heart J 2020 04 15;222:8-14. Epub 2020 Jan 15.

Division of Cardiology, Department of Medicine, University of North Carolina, Chapel Hill, NC.

Background: The prevalence of renal disease in cardiac intensive care units (CICUs) is increasing, but little is known about the utilization, concurrent therapies, and outcomes of patients requiring acute renal replacement therapy (RRT) in this specialized environment.

Methods: In the Critical Care Cardiology Trials Network, 16 centers submitted data on CICU admissions including acute RRT (defined as continuous renal replacement therapy and/or acute intermittent dialysis).

Results: Among 2,985 admissions, 178 (6.0%; interhospital range 1.0%-16.0%) received acute RRT. Patients receiving RRT, versus not, were more commonly admitted for cardiogenic shock (15.7% vs 4.2%, P < .01), cardiac arrest (9.6% vs 3.7%, P < .01), and acute general medical diagnoses (10.7% vs 5.8%, P < .01), whereas acute coronary syndromes (16.9% vs 32.1%, P < .01) were less frequent. Variables independently associated with acute RRT included diabetes, heart failure, liver disease, severe valvular disease, shock, cardiac arrest, hypertension, and younger age. In patients receiving acute RRT, versus not, advanced therapies including mechanical ventilation (55.6% vs 18.0%), vasoactive support (73.0% vs 35.2%), invasive hemodynamic monitoring (59.6% vs 29.2%), and mechanical circulatory support (27.5% vs 8.4%) were more common. Acute RRT was associated with higher in-hospital mortality (42.1% vs 9.3%, adjusted odds ratio 3.74, 95% CI, 2.52-5.53) and longer median length of stay (10.0 vs 5.3 days, P < .01). In conclusion, acute RRT in contemporary CICUs was associated with the provision of other advanced therapies and lower survival.

Conclusions: These data underscore the risks associated with the provision of renal support in patients with primary cardiovascular problems and the need to develop standardized indications and potential futility measures in this specialized population.
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http://dx.doi.org/10.1016/j.ahj.2020.01.005DOI Listing
April 2020

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis.

J Med Genet 2020 07 27;57(7):454-460. Epub 2020 Jan 27.

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia

Background: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown.

Methods: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays.

Results: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, (family 1) and (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate.

Conclusion: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes and , demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.
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http://dx.doi.org/10.1136/jmedgenet-2019-106700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361035PMC
July 2020

Case report: North Carolina macular dystrophy misdiagnosed as congenital ocular toxoplasmosis.

Mol Vis 2019 14;25:731-733. Epub 2019 Nov 14.

Department of Ophthalmology, The Women's and Children's Hospital, Adelaide, South Australia, Australia.

Purpose: This report discusses a case of North Carolina macular dystrophy (NCMD) in a 7-year-old boy initially diagnosed as congenital toxoplasmosis. Genetic testing was performed on the child and his family after the suspicion of NCMD was raised by the treating ophthalmologist. This case report highlights the similarities between congenital toxoplasmosis and NCMD.

Methods: DNA was collected from the family with consent and underwent comparative genomic hybridization and Sanger sequencing.

Results: Genetic testing identified a previously reported single base substitution (chromosome 6: 99,593,111 (G>C) NC_000006.11(GRCh38):g.100040987G>C), which confirms a diagnosis of NCMD.

Conclusions: We believe this is the first confirmed case of NCMD in Australia. This case highlights the similarities between NCMD and more commonly recognized conditions, such as ocular toxoplasmosis, and raises the question; How many other cases are misdiagnosed as ocular toxoplasmosis?
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857771PMC
June 2020

The impact of cation structure upon the acidity of triazolium salts in dimethyl sulfoxide.

Org Biomol Chem 2019 12;18(1):66-75

School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.

A series of triazolium salts, selected for their varying electronic and steric properties, were prepared and their pKa values were determined in DMSO at 25 °C using the bracketing indicator method. The effect of each systematic structural variation upon the acidity of the triazolium cation has been considered, in particular examining the effects of systematically altering electronic properties, quantified through the use of Hammett σ parameters. The first pKa value for an azolium salt that generates a mesionic carbene is also reported. These new data allow for the selection of appropriate bases for the deprotonation of such triazolium salts and the potential to correlate the pKa values determined herein with the nucleophilicity of the corresponding carbenes.
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http://dx.doi.org/10.1039/c9ob02258aDOI Listing
December 2019

Neurogenic Stunned Myocardium in Severe Neurological Injury.

Curr Neurol Neurosci Rep 2019 11 13;19(11):90. Epub 2019 Nov 13.

Department of Critical Care Medicine, MedStar Washington Hospital Center, 110 Irving St, NW, Rm 4B42, Washington, DC, 20010, USA.

Purpose Of Review: Neurogenic stunned myocardium (NSM) is a poorly recognized cardiac manifestation of neurological illness. This review addresses the contemporary understanding of NSM pathophysiology, epidemiology, diagnosis, and clinical management.

Recent Findings: While the precise pathophysiology and diagnosis remain unclear, NSM is phenotypically atypical stress cardiomyopathy that can be partially attributed to excess catecholaminergic toxicity. NSM is a diagnosis of exclusion where electrocardiography, echocardiography, and cardiac biomarkers are frequently abnormal. Clinical expertise is crucial to evaluate and differentiate NSM from acute coronary syndrome and in the evaluation of potential cardiac transplantation donors after unsalvageable severe neurological injury. Neurogenic stunned myocardium is a relatively common and clinically impactful condition. More research is needed, particularly to refine clinical prognostication of NSM and rule out intrinsic cardiac injury in order to optimize donor candidacy in the event of brain death.
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http://dx.doi.org/10.1007/s11910-019-0999-7DOI Listing
November 2019

Clinical Practice Patterns in Temporary Mechanical Circulatory Support for Shock in the Critical Care Cardiology Trials Network (CCCTN) Registry.

Circ Heart Fail 2019 11 11;12(11):e006635. Epub 2019 Nov 11.

Levine Cardiac Intensive Care Unit, TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (D.D.B., V.M.B.-Z., E.A.B., J.-G.P., D.A.M.).

Background: Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units.

Methods: The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions.

Results: Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%-50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%-100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use.

Conclusions: There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008928PMC
November 2019

Novel KIT mutation presenting as marked lentiginosis.

Pediatr Dermatol 2019 Nov 9;36(6):922-925. Epub 2019 Sep 9.

Paediatric and Reproductive Genetic Unit, Women's and Children's Hospital, North Adelaide, South Australia, Australia.

Although lentigines are usually benign, they can be associated with a number of genetic syndromes in which neoplasms and other multi-system pathological processes occur. Here, we report the case of a 6-year-old girl who presented with atypical lentiginosis and hyperpigmentation caused by a de novo genetic variant in the KIT gene.
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http://dx.doi.org/10.1111/pde.13952DOI Listing
November 2019