12 results on '"Whittle E"'
Search Results
2. Thunberia alata 16:0-ACP desaturase
- Author
-
Guy, J.E., primary, Whittle, E., additional, Cai, Y., additional, Chai, J., additional, Lindqvist, Y., additional, and Shanklin, J., additional
- Published
- 2021
- Full Text
- View/download PDF
3. Paediatric percutaneous bone anchored hearing aid implant failures: Comparing the experience of a tertiary centre with a systematic review of the literature and meta-analysis.
- Author
-
Bradley M, Shields C, Sabourn R, Whittle E, Boyd R, Bruce IA, and Nichani J
- Subjects
- Humans, Child, Bone-Anchored Prosthesis, Retrospective Studies, Hearing Loss, Conductive surgery, Hearing Loss, Conductive etiology, Child, Preschool, Adolescent, Bone Conduction, Male, Female, Hearing Loss, Mixed Conductive-Sensorineural surgery, Hearing Aids, Prosthesis Failure, Tertiary Care Centers
- Abstract
Background: Despite the proven audiological benefits of Percutaneous Bone Anchored Hearing Aids (BAHAs) in paediatric patients with conductive or mixed hearing loss, their adoption has been limited due to concerns over implant failure and associated complications. This paper conducts a systematic review and meta-analysis to assess the prevalence of implant failure in paediatric populations, combined with a case series from our tertiary referral centre., Methods: A comprehensive literature search identified 562 articles, from which 34 were included in the review, covering 1599 implants in 1285 patients. Our retrospective case series included consecutive patients from our tertiary referral centre who underwent percutaneous BAHA implantation from 2003-2019., Results: Meta-analysis revealed an overall implant failure rate of 11%, predominantly attributed to traumatic extrusion. Our retrospective case series comprised 104 implantations in 76 patients, with a 4.8% failure rate., Discussion: Factors contributing to the lower-than-expected failure rates in the case series likely included consistent use of 4 mm fixtures from a single manufacturer and older age at implantation. The study underscores the need for standardised reporting formats in bone conduction implants research, given the systematic review's limitations in study design heterogeneity, especially with the expected rise in the adoption of novel active devices.
- Published
- 2024
- Full Text
- View/download PDF
4. Application of machine learning models to animal health pharmacovigilance: A proof-of-concept study.
- Author
-
Whittle E, Novotny MJ, McCaul SP, Moeller F, Junk M, Giraldo C, O'Gorman M, de Chenu C, and Dzavan P
- Subjects
- Animals, Pharmacovigilance, Machine Learning, Drug-Related Side Effects and Adverse Reactions veterinary
- Abstract
Machine learning (ML) models were applied to pharmacovigilance (PV) data in a two-component proof-of-concept study. PV data were partitioned into Training, Validation, and Holdout datasets for model training and selection. During the first component ML models were challenged to identify factors in individual case safety reports (ICSRs) involving spinosad and neurological and ocular clinical signs. The target feature for the models were these clinical signs that were disproportionately reported for spinosad. The endpoints were normalized coefficient values representing the relationship between the target feature and ICSR free text fields. The deployed model accurately identified the risk factors "demodectic," "demodicosis," and "ivomec." In the second component, the ML models were trained to identify high quality and complete ICSRs free of confounders. The deployed model was presented with an external Test dataset of six ICSRs, one that was complete, of high quality, and devoid of confounders, and five that were not. The endpoints were model-generated probabilities for the ICSRs. The deployed ML model accurately identified the ICSR of interest with a greater than 10-fold higher probability score. Although narrow in scope, the study supports further investigation and potential application of ML models to animal health PV data., (© 2023 John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
5. Blinded comparison of computed tomography, ultrasound and needle methods to measure skin flap thickness for cochlear implantation.
- Author
-
Abrar R, de Estibariz UM, Whittle E, Hornby S, O'Driscoll M, Freeman S, and Stapleton E
- Subjects
- Adult, Male, Female, Humans, Middle Aged, Prospective Studies, Tomography, X-Ray Computed methods, Ultrasonography, Cochlear Implantation methods, Cochlear Implants
- Abstract
Purpose: Patient suitability for cochlear implant (CI) devices compatible with magnetic resonance imaging and CI processor configuration is dependent on their retro-auricular skin flap thickness. This is typically measured intra-operatively using a needle and therefore patients are not guaranteed their implant of choice prior to surgery. We aimed to identify an accurate method to measure skin flap thickness pre-operatively to streamline CI selection and simplify the consent process., Methods: Blinded prospective skin flap thickness measurements for patients undergoing CI surgery were recorded using pre-operative computed tomography (CT) and ultrasound (US), and intraoperative needle measurement., Results: Fifty-six adult patients (36 females, 20 males; mean age 59 years) were included. The mean flap thickness was measured highest by CT (6.9 mm, 95% CI 6.5-7.3 mm), followed by US (6.3 mm, 95% CI 5.9-6.7 mm) and lastly needle (5.5 mm, 95% CI 5.1-5.9 mm) ( p < 0.0001). A strong positive correlation ( p < 0.001) was noted between all three modalities: CT vs needle ( r = 0.869), US vs needle ( r = 0.865), and CT vs US ( r = 0.849)., Conclusion: Accurate, non-invasive measurement of skin flap thickness prior to CI surgery can be achieved using CT or US. We recommend the routine use of US in the outpatient clinic to minimise unnecessary radiation exposure.
- Published
- 2023
- Full Text
- View/download PDF
6. Use of Optical Genome Mapping to Detect Structural Variants in Neuroblastoma.
- Author
-
Barford RG, Whittle E, Weir L, Fong FC, Goodman A, Hartley HE, Allinson LM, and Tweddle DA
- Abstract
Background: Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of paediatric cancer deaths. Multiple genetic abnormalities have been identified as prognostically significant in neuroblastoma patients. Optical genome mapping (OGM) is a novel cytogenetic technique used to detect structural variants, which has not previously been tested in neuroblastoma. We used OGM to identify copy number and structural variants (SVs) in neuroblastoma which may have been missed by standard cytogenetic techniques., Methods: Five neuroblastoma cell lines (SH-SY5Y, NBLW, GI-ME-N, NB1691 and SK-N-BE2(C)) and two neuroblastoma tumours were analysed using OGM with the Bionano Saphyr
® instrument. The results were analysed using Bionano Access software and compared to previous genetic analyses including G-band karyotyping, FISH (fluorescent in situ hybridisation), single-nucleotide polymorphism (SNP) array and RNA fusion panels for cell lines, and SNP arrays and whole genome sequencing (WGS) for tumours., Results: OGM detected copy number abnormalities found using previous methods and provided estimates for absolute copy numbers of amplified genes. OGM identified novel SVs, including fusion genes in two cell lines of potential clinical significance., Conclusions: OGM can reliably detect clinically significant structural and copy number variations in a single test. OGM may prove to be more time- and cost-effective than current standard cytogenetic techniques for neuroblastoma.- Published
- 2023
- Full Text
- View/download PDF
7. 3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1.
- Author
-
Ball N, Duncan S, Zhang Y, Payet R, Piec I, Whittle E, Tang JCY, Schoenmakers I, Lopez B, Chipchase A, Kumar A, Perry L, Maxwell H, Ding Y, Fraser WD, and Green D
- Subjects
- Humans, Chromatography, Liquid, Hypercalciuria genetics, Mutation genetics, Tandem Mass Spectrometry, Vitamin D, 3' Untranslated Regions genetics, Hypercalcemia genetics, Vitamin D3 24-Hydroxylase genetics
- Abstract
Loss-of-function mutations in the CYP24A1 protein-coding region causing reduced 25 hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D (1,25(OH)
2 D) catabolism have been observed in some cases of infantile hypercalcemia type 1 (HCINF1), which can manifest as nephrocalcinosis, hypercalcemia and adult-onset hypercalciuria, and renal stone formation. Some cases present with apparent CYP24A1 phenotypes but do not exhibit pathogenic mutations. Here, we assessed the molecular mechanisms driving apparent HCINF1 where there was a lack of CYP24A1 mutation. We obtained blood samples from 47 patients with either a single abnormality of no obvious cause or a combination of hypercalcemia, hypercalciuria, and nephrolithiasis as part of our metabolic and stone clinics. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine serum vitamin D metabolites and direct sequencing to confirm CYP24A1 genotype. Six patients presented with profiles characteristic of altered CYP24A1 function but lacked protein-coding mutations in CYP24A1. Analysis upstream and downstream of the coding sequence showed single nucleotide variants (SNVs) in the CYP24A1 3' untranslated region (UTR). Bioinformatics approaches revealed that these 3' UTR abnormalities did not result in microRNA silencing but altered the CYP24A1 messenger RNA (mRNA) secondary structure, which negatively impacted translation. Our experiments showed that mRNA misfolding driven by these 3' UTR sequence-dependent structural elements was associated with normal 25OHD but abnormal 1,25(OH)2 D catabolism. Using CRISPR-Cas9 gene editing, we developed an in vitro mutant model for future CYP24A1 studies. Our results form a basis for future studies investigating structure-function relationships and novel CYP24A1 mutations producing a semifunctional protein. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)- Published
- 2023
- Full Text
- View/download PDF
8. A systemic review of the role of enterotoxic Bacteroides fragilis in colorectal cancer.
- Author
-
Scott N, Whittle E, Jeraldo P, and Chia N
- Subjects
- Animals, Humans, Mice, Bacteroides fragilis metabolism, Bacterial Toxins metabolism, Bacterial Toxins toxicity, Bacteroides Infections complications, Bacteroides Infections diagnosis, Bacteroides Infections pathology, Colorectal Neoplasms pathology
- Abstract
Enterotoxigenic Bacteroides fragilis (ETBF) has received significant attention for a possible association with, or causal role in, colorectal cancer (CRC). The goal of this review was to assess the status of the published evidence supporting (i) the association between ETBF and CRC and (ii) the causal role of ETBF in CRC. PubMed and Scopus searches were performed in August 2021 to identify human, animal, and cell studies pertaining to the role of ETBF in CRC. Inclusion criteria included the use of cell lines, mice, exposure to BFT or ETBF, and detection of bft. Review studies were excluded, and studies were limited to the English language. Quality of study design and risk of bias analysis was performed on the cell, animal, and human studies using ToxRTools, SYRCLE, and NOS, respectively. Ninety-five eligible studies were identified, this included 22 human studies, 24 animal studies, 43 cell studies, and 6 studies that included both cells and mice studies. We found that a large majority of studies supported an association or causal role of ETBF in CRC, as well as high levels of study bias was detected in the in vitro and in vivo studies. The high-level heterogeneity in study design and reporting made it difficult to synthesize these findings into a unified conclusion, suggesting that the need for future studies that include improved mechanistic models, longitudinal in vitro and in vivo evidence, and appropriate control of confounding factors will be required to confirm whether ETBF has a direct role in CRC etiopathogenesis., (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
- Full Text
- View/download PDF
9. Regioselectivity mechanism of the Thunbergia alata Δ6-16:0-acyl carrier protein desaturase.
- Author
-
Guy JE, Cai Y, Baer MD, Whittle E, Chai J, Yu XH, Lindqvist Y, Raugei S, and Shanklin J
- Subjects
- Gene Expression Regulation, Plant, Genes, Plant, Metabolic Networks and Pathways, Molecular Structure, Structure-Activity Relationship, Acanthaceae genetics, Acanthaceae metabolism, Acyl Carrier Protein genetics, Acyl Carrier Protein metabolism, Plastids genetics, Plastids metabolism
- Abstract
Plant plastidial acyl-acyl carrier protein (ACP) desaturases are a soluble class of diiron-containing enzymes that are distinct from the diiron-containing integral membrane desaturases found in plants and other organisms. The archetype of this class is the stearoyl-ACP desaturase which converts stearoyl-ACP into oleoyl (18:1Δ9cis)-ACP. Several variants expressing distinct regioselectivity have been described including a Δ6-16:0-ACP desaturase from black-eyed Susan vine (Thunbergia alata). We solved a crystal structure of the T. alata desaturase at 2.05 Å resolution. Using molecular dynamics (MD) simulations, we identified a low-energy complex between 16:0-ACP and the desaturase that would position C6 and C7 of the acyl chain adjacent to the diiron active site. The model complex was used to identify mutant variants that could convert the T. alata Δ6 desaturase to Δ9 regioselectivity. Additional modeling between ACP and the mutant variants confirmed the predicted regioselectivity. To validate the in-silico predictions, we synthesized two variants of the T. alata desaturase and analyzed their reaction products using gas chromatography-coupled mass spectrometry. Assay results confirmed that mutants designed to convert T. alata Δ6 to Δ9 selectivity exhibited the predicted changes. In complementary experiments, variants of the castor desaturase designed to convert Δ9 to Δ6 selectivity lost some of their Δ9 desaturation ability and gained the ability to desaturate at the Δ6 position. The computational workflow for revealing the mechanistic understanding of regioselectivity presented herein lays a foundation for designing acyl-ACP desaturases with novel selectivities to increase the diversity of monoenes available for bioproduct applications., (Published by Oxford University Press on behalf of American Society of Plant Biologists 2021. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2022
- Full Text
- View/download PDF
10. "Answers in hours": A prospective clinical study using nanopore sequencing for bile duct cultures.
- Author
-
Yonkus JA, Whittle E, Alva-Ruiz R, Abdelrahman AM, Horsman SE, Suh GA, Cunningham SA, Nelson H, Grotz TE, Smoot RL, Cleary SP, Nagorney DM, Kendrick ML, Patel R, Truty MJ, and Chia N
- Subjects
- Adult, Aged, Bile microbiology, Feasibility Studies, Female, Humans, Male, Middle Aged, Prospective Studies, Time Factors, Young Adult, Bile Ducts microbiology, Intraoperative Care, Nanopore Sequencing, Pancreatectomy, Pancreaticoduodenectomy
- Abstract
Background: Surgical site infection is a major source of morbidity in patients undergoing pancreatic head resection and is often from organisms in intraoperative bile duct cultures. As such, many institutions use prolonged prophylactic antibiotics and tailor based on bile duct cultures. However, standard cultures take days, leaving many patients unnecessarily on prolonged antibiotics. Nanopore sequencing can provide data in hours and, thus, has the potential to improve antibiotic stewardship. The present study investigates the feasibility of nanopore sequencing in intraoperative bile samples., Methods: Patients undergoing pancreatic head resection were included. Intra-operative bile microbial profiles were determined with standard cultures and nanopore sequencing. Antibiotic recommendations were generated, and time-to-results determined for both methods. Organism yields, resistance patterns, antibiotic recommendations, and costs were compared., Results: Out of 42 patients, 22 (52%) had samples resulting in positive standard cultures. All positive standard cultures had microbes detected using nanopore sequencing. All 20 patients with negative standard cultures had negative nanopore sequencing. Nanopore sequencing detected more bacterial species compared to standard cultures (10.5 vs 4.4, p < 0.05) and more resistance genotypes (10.3 vs 2.7, p < 0.05). Antimicrobial recommendations based on nanopore sequencing provided coverage for standard cultures in 27 out of 44 (61%) samples, with broader coverage recommended by nanopore sequencing in 13 out of 27 (48%) of these samples. Nanopore sequencing results were faster (8 vs 98 hours) than standard cultures but had higher associated costs ($165 vs $38.49)., Conclusion: Rapid microbial profiling with nanopore sequencing is feasible with broader organism and resistance profiling compared to standard cultures. Nanopore sequencing has perfect negative predictive value and can potentially improve antibiotic stewardship; thus, a randomized control trial is under development., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
11. Optimizing Nanopore Sequencing for Rapid Detection of Microbial Species and Antimicrobial Resistance in Patients at Risk of Surgical Site Infections.
- Author
-
Whittle E, Yonkus JA, Jeraldo P, Alva-Ruiz R, Nelson H, Kendrick ML, Grys TE, Patel R, Truty MJ, and Chia N
- Subjects
- Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial genetics, Humans, Microbial Sensitivity Tests, Surgical Wound Infection diagnosis, Nanopore Sequencing
- Abstract
Surgical site infections (SSI) are a significant burden to patients and health care systems. We evaluated the use of Nanopore sequencing (NS) to rapidly detect microbial species and antimicrobial resistance (AMR) genes present in intraoperative bile aspirates. Bile aspirates from 42 patients undergoing pancreatic head resection were included. Three methods of DNA extraction using mechanical cell lysis or protease cell lysis were compared to determine the optimum method of DNA extraction. The impact of host DNA depletion, sequence run duration, and use of different AMR gene databases was also assessed. To determine clinical value, NS results were compared to standard culture (SC) results. NS identified microbial species in all culture positive samples. Mechanical lysis improved NS detection of cultured species from 60% to 76%, enabled detection of fungal species, and increased AMR predictions. Host DNA depletion improved detection of streptococcal species and AMR correlation with SC. Selection of AMR database influenced the number of AMR hits and resistance profile of 13 antibiotics. AMR prediction using CARD and ResFinder 4.1 correctly predicted 79% and 81% of the bile antibiogram, respectively. Sequence run duration positively correlated with detection of AMR genes. A minimum of 6 h was required to characterize the biliary microbes, resulting in a turnaround time of 14 h. Rapid identification of microbial species and AMR genes can be achieved by NS. NS results correlated with SC, suggesting that NS may be useful in guiding early antimicrobial therapy postsurgery. IMPORTANCE Surgical site infections (SSI) are a significant burden to patients and health care systems. They increase mortality rates, length of hospital stays, and associated health care costs. To reduce the risk of SSI, surgical patients are administered broad-spectrum antibiotics that are later adapted to target microbial species detected at the site of surgical incision. Use of broad-spectrum antibiotics can be harmful to the patient. We wanted to develop a rapid method of detecting microbial species and their antimicrobial resistance phenotypes. We developed a method of detecting microbial species and predicting resistance phenotypes using Nanopore sequencing. Results generated using Nanopore sequencing were similar to current methods of detection but were obtained in a significantly shorter amount of time. This suggests that Nanopore sequencing could be used to tailor antibiotics in surgical patients and reduce use of broad-spectrum antibiotics.
- Published
- 2022
- Full Text
- View/download PDF
12. Cadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia.
- Author
-
Baker A, Clarke L, Donovan P, P J Ungerer J, Hartel G, Bruxner G, Cocchi L, Gordon A, Moudgil V, Robinson G, Roy D, Sohal R, Whittle E, and Scott JG
- Subjects
- Australia, Double-Blind Method, Humans, Schizophrenia, Treatment-Resistant, Sodium Benzoate adverse effects, Treatment Outcome, Antipsychotic Agents adverse effects, Schizophrenia diagnosis, Schizophrenia drug therapy
- Abstract
Background: Schizophrenia is a persistent psychotic disorder often accompanied by severe disability and premature mortality. New pharmacological treatments are urgently needed. Sodium benzoate, a common food preservative holds potential to be an effective, accessible treatment for schizophrenia, though the optimal dosing and mechanism of action of the compound requires further investigation., Methods: Individuals with persistent treatment-refractory schizophrenia (n=52) will be recruited. Patients will be randomised in a 1:1:1:1 ratio to receive treatment of one of three active doses (1000, 2000 or 4000 mg daily) of sodium benzoate or placebo for 6 weeks duration. The primary outcome measurement is change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measurements are PANSS subscales, Global Assessment of Function (GAF), Clinical Global Impression (CGI) and Patient Global Impression (PGI-I). Change in concentrations of peripheral amino acids (D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate), plasma sodium benzoate, plasma catalase, 3-nitrotyrosine, malondialdehyde and high-sensitivity C-reactive protein (hs-CRP) will be determined as tertiary measures., Discussion: This trial seeks to build upon previous research indicating potential efficacy of sodium benzoate for reduction of symptoms in individuals with treatment-refractory schizophrenia. The trial aims to improve the understanding of the mechanism of action of the compound., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000327886 . Registered on 23 March 2021., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.