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Article ; Online: Late changes in blood-brain barrier permeability in a rat tMCAO model of stroke detected by gadolinium-enhanced MRI.

Morgan, Catherine A / Mesquita, Michel / Ashioti, Maria / Beech, John S / Williams, Steve C R / Irving, Elaine / Cash, Diana

Neurological research

2020 Volume 42, Issue 10, Page(s) 844–852

Abstract: Objectives: After cerebral ischaemia the blood-brain barrier (BBB) may be compromised and this has been observed in both clinical and preclinical studies. The timing of BBB disruption after ischaemia has long been considered to be biphasic, however some ...

Abstract	Objectives: After cerebral ischaemia the blood-brain barrier (BBB) may be compromised and this has been observed in both clinical and preclinical studies. The timing of BBB disruption after ischaemia has long been considered to be biphasic, however some groups contest this view. Therefore, the purpose of this study was to characterize the BBB permeability timecourse in a rat model at both acute and chronic time points. Methods: Unilateral transient middle cerebral artery occlusion (tMCAO) was performed in 15 male Sprague Dawley rats. Change in T1-weighted MR signal before and after an injection of gadolinium-based contrast agent was calculated voxelwise to derive a BBB permeability index (BBBPI) at both early (6 h, 12 h, and 24 h) and late (7 and 14 days) time points. Results: As expected, BBBPI in the non-lesioned ROI was not significantly different from pre-occlusion baseline at any time point. However, BBBPI in the ipsilateral (lesioned) ROI was statistically different to baseline at day 7 (p < 0.001) and day 14 (p < 0.01) post-tMCAO. There was a small, but not-significant increase in BBBPI in the earlier phase (at 6 hours). Discussion: Our results indicate a significant late opening of the BBB. This is important as the majority of previous studies have only characterised an early acute BBB permeability in ischemia. However, the later period of increased permeability may indicate an optimal time for drug delivery across the BBB, when it is especially suited to drugs targeting delayed processes.
MeSH term(s)	Animals ; Blood-Brain Barrier/diagnostic imaging ; Blood-Brain Barrier/metabolism ; Capillary Permeability ; Contrast Media ; Disease Models, Animal ; Gadolinium ; Image Enhancement ; Infarction, Middle Cerebral Artery/diagnostic imaging ; Infarction, Middle Cerebral Artery/metabolism ; Magnetic Resonance Imaging/methods ; Male ; Rats, Sprague-Dawley ; Stroke/diagnostic imaging ; Stroke/metabolism ; Time Factors
Chemical Substances	Contrast Media ; Gadolinium (AU0V1LM3JT)
Language	English
Publishing date	2020-06-30
Publishing country	England
Document type	Journal Article
ZDB-ID	424428-x
ISSN	1743-1328 ; 0161-6412
ISSN (online)	1743-1328
ISSN	0161-6412
DOI	10.1080/01616412.2020.1786637
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Article ; Online: The GetReal Trial Tool: design, assess and discuss clinical drug trials in light of Real World Evidence generation.

Zuidgeest, Mira G P / Goetz, Iris / Meinecke, Anna-Katharina / Boateng, Daniel / Irving, Elaine A / van Thiel, Ghislaine J M / Welsing, Paco M J / Oude-Rengerink, Katrien / Grobbee, Diederick E

Journal of clinical epidemiology

2021 Volume 149, Page(s) 244–253

Abstract: Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake ... ...

Abstract	Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the "GetReal Trial Tool," an easy-to-use online interface, which allows users to assess the impact of design choices on generalizability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organizations, and regulators. The aim is to help researchers optimize trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.
MeSH term(s)	Humans ; Data Collection/methods ; Drug Evaluation ; Research Design ; Research Personnel ; Clinical Trials as Topic
Language	English
Publishing date	2021-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639306-8
ISSN	1878-5921 ; 0895-4356
ISSN (online)	1878-5921
ISSN	0895-4356
DOI	10.1016/j.jclinepi.2021.12.019
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Article ; Online: Cortical somatostatin interneuron subtypes form cell-type-specific circuits.

Wu, Sherry Jingjing / Sevier, Elaine / Dwivedi, Deepanjali / Saldi, Giuseppe-Antonio / Hairston, Ariel / Yu, Sabrina / Abbott, Lydia / Choi, Da Hae / Sherer, Mia / Qiu, Yanjie / Shinde, Ashwini / Lenahan, Mackenzie / Rizzo, Daniella / Xu, Qing / Barrera, Irving / Kumar, Vipin / Marrero, Giovanni / Prönneke, Alvar / Huang, Shuhan /

Kullander, Klas / Stafford, David A / Macosko, Evan / Chen, Fei / Rudy, Bernardo / Fishell, Gord

Neuron

2023 Volume 111, Issue 17, Page(s) 2675–2692.e9

Abstract: The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron ... ...

Abstract	The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. Although there is evidence that this diversity is functionally relevant, the circuit implications of this diversity are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes and found that each subtype possesses a unique laminar organization and stereotyped axonal projection pattern. Using these strategies, we examined the afferent and efferent connectivity of three subtypes (two Martinotti and one non-Martinotti) and demonstrated that they possess selective connectivity with intratelecephalic or pyramidal tract neurons. Even when two subtypes targeted the same pyramidal cell type, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin interneurons form cell-type-specific cortical circuits.
MeSH term(s)	Interneurons/physiology ; Neurons/physiology ; Pyramidal Cells/physiology ; Axons/metabolism ; Somatostatin/metabolism ; Parvalbumins/metabolism
Chemical Substances	Somatostatin (51110-01-1) ; Parvalbumins
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.05.032
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Article ; Online: Patient and healthcare professional experiences of the Salford Lung Studies: qualitative insights for future effectiveness trials.

Gemzoe, Kim / Crawford, Rebecca / Caress, Ann / McCorkindale, Sheila / Conroy, Rebecca / Collier, Susan / Doward, Lynda / Vekaria, Renu M / Worsley, Sally / Leather, David A / Irving, Elaine

Trials

2020 Volume 21, Issue 1, Page(s) 798

Abstract: Background: Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the challenges/ ... ...

Abstract	Background: Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the challenges/opportunities for patient and healthcare professional (HCP) engagement in clinical research is needed to enhance participation and trial experience. In this study, we explored patient and HCP drivers for, and experiences of, participation in the Salford Lung Studies (SLS), and their views on future trial participation and the overall value of such trials. Methods: This was a qualitative study set in Salford, UK, comprising patient telephone interviews (N = 10) and HCP advisory boards (one with general practitioners [GPs], one with practice managers [PMs]); all individuals had participated in the SLS. Semi-structured telephone interviews were recorded, transcribed and analysed thematically. Advisory board meetings were analysed based on transcriptions of audio recordings and field notes. Results: For patients, key positive aspects of the SLS were the ease/convenience of study assessments and excellent relationships with study nurses. GPs and PMs considered the SLS to be well-organized and highlighted the value of research nurse support; they also described minor challenges relating to trial systems, initial financial strain on practices and staff turnover. All participants indicated that they were very likely to participate in future trials, citing a design closely aligned with routine care practice as essential. Several strategies to encourage trial participation were suggested, such as clearly communicating benefits to patients and ensuring flexible study assessments. Conclusions: Patients and HCPs had positive experiences of the SLS. The study design, closely aligned with routine care, was considered important to their high likelihood of participating in future trials. The experiences of patients and HCPs in the SLS provide valuable insights that will help inform future best practice in the design and conduct of future real-world effectiveness RCTs in primary care. The detailed first-hand experiences of HCPs will be of significant value to others considering engaging in clinical research and participating in effectiveness RCTs.
MeSH term(s)	Delivery of Health Care ; Health Personnel ; Humans ; Lung ; Primary Health Care ; Qualitative Research
Language	English
Publishing date	2020-09-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2040523-6
ISSN	1745-6215 ; 1468-6694 ; 1468-6708
ISSN (online)	1745-6215 ; 1468-6694
ISSN	1468-6708
DOI	10.1186/s13063-020-04655-x
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Article ; Online: Symptomatic treatment of Alzheimer's disease: identification of biomarkers to aid translation from bench to bedside.

Irving, Elaine A / Upton, Neil

Biomarkers in medicine

2007 Volume 1, Issue 1, Page(s) 93–110

Abstract: In the absence of robust pharmacodynamic markers, the potential success of novel therapeutic agents for the symptomatic relief of Alzheimer's disease is largely unknown until the drugs enter relatively large studies, assessing clinical outcome over a 6- ... ...

Abstract	In the absence of robust pharmacodynamic markers, the potential success of novel therapeutic agents for the symptomatic relief of Alzheimer's disease is largely unknown until the drugs enter relatively large studies, assessing clinical outcome over a 6-month period. In order to increase the efficiency of future clinical development there is, therefore, a need to identify pharmacodynamic markers of drug response, pharmacodynamic models that allow early prediction of efficacy and markers to aid the stratification of the patient population. Using literature available from cholinesterase inhibitors, memantine and Ginkgo biloba, this review focuses on the identification of potential pharmacodynamic markers/models and highlights the utility of these end points throughout the drug discovery process, from preclinical to clinical development.
Language	English
Publishing date	2007-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2481014-9
ISSN	1752-0371 ; 1752-0363
ISSN (online)	1752-0371
ISSN	1752-0363
DOI	10.2217/17520363.1.1.93
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Article ; Online: Baseline characteristics of participants in the NAVKIDS

Guha, Chandana / Khalid, Rabia / van Zwieten, Anita / Francis, Anna / Hawley, Carmel M / Jauré, Allison / Teixeira-Pinto, Armando / Mallard, Alistair R / Bernier-Jean, Amelie / Johnson, David W / Hahn, Deirdre / Reidlinger, Donna / Pascoe, Elaine M / Ryan, Elizabeth G / Mackie, Fiona / McCarthy, Hugh J / Craig, Jonathan C / Varghese, Julie / Kiriwandeniya, Charani /

Howard, Kirsten / Larkins, Nicholas G / Macauley, Luke / Walker, Amanda / Howell, Martin / Irving, Michelle / Caldwell, Patrina H Y / Woodleigh, Reginald / Jesudason, Shilpanjali / Carter, Simon A / Kennedy, Sean E / Alexander, Stephen I / McTaggart, Steven / Wong, Germaine

Pediatric nephrology (Berlin, Germany)

2022 Volume 38, Issue 5, Page(s) 1577–1590

Abstract: Background: Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing ... ...

Abstract	Background: Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing health services through care coordination. This trial aims to determine the effectiveness of a patient navigator program in children with CKD. Methods: The NAVKIDS Results: The trial completed recruitment in October 2021 with expected completion of follow-up by October 2022. There were 162 patients enrolled with 80 and 82 patients randomized to the immediate intervention and waitlisted groups, respectively. Fifty-eight (36%) participants were from regional/remote areas, with a median (IQR) age of 9.5 (5.0, 13.0) years, 46% were of European Australian ethnicity, and 65% were male. A total of 109 children (67%) had CKD stages 1-5, 42 (26%) were transplant recipients, and 11 (7%) were receiving dialysis. Conclusion: The NAVKIDS
MeSH term(s)	Humans ; Male ; Child ; Female ; Patient Navigation ; Quality of Life ; Renal Dialysis ; Australia ; Renal Insufficiency, Chronic/therapy
Language	English
Publishing date	2022-10-20
Publishing country	Germany
Document type	Randomized Controlled Trial ; Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-022-05772-2
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Article ; Online: Magnetic Microdevices for MRI-Based Detection of SARS-CoV-2 Viruses.

Mair, Lamar O / Hale, Olivia / Jafari, Sahar / Chen, Cheng / Udalov, Oleg / Probst, Roland / Baum, Ittai / Hevaganinge, Anjana / Yi Wang, Elaine / Rodriguez, Olga C / Albanese, Christopher / Fricke, Stanley T / Weinberg, Irving N

IEEE open journal of engineering in medicine and biology

2020 Volume 1, Page(s) 265–267

Abstract: Goal: To develop a micron-scale device that can operate as an MRI-based reporter for the presence of SARS-CoV-2 virus.: Methods: Iron rod microdevices were constructed via template-guided synthesis and suspended in phosphate buffered saline (PBS). ... ...

Abstract	Goal: To develop a micron-scale device that can operate as an MRI-based reporter for the presence of SARS-CoV-2 virus. Methods: Iron rod microdevices were constructed via template-guided synthesis and suspended in phosphate buffered saline (PBS). Heat-inactivated SARS-CoV-2 viruses were added to the samples and imaged with low-field MRI. Results: MRI of microdevices and viruses showed decreased signal intensity at low concentrations of viruses that recovered at higher concentrations. Electron micrographs suggest that reduced MRI intensity may be due to concentration-dependent shielding of water protons from local magnetic inhomogeneities caused by the iron microdevices. Conclusions: The preliminary results presented in this letter provide justification for further studies exploring the potential diagnostic role of magnetic microdevices in assessing the presence and concentration of SARS-CoV-2 viruses.
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Journal Article
ISSN	2644-1276
ISSN (online)	2644-1276
DOI	10.1109/ojemb.2020.3026234
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Article ; Online: Patient and healthcare professional experiences of the Salford Lung Studies

Kim Gemzoe / Rebecca Crawford / Ann Caress / Sheila McCorkindale / Rebecca Conroy / Susan Collier / Lynda Doward / Renu M. Vekaria / Sally Worsley / David A. Leather / Elaine Irving

Trials, Vol 21, Iss 1, Pp 1-

qualitative insights for future effectiveness trials

2020 Volume 12

Abstract: Abstract Background Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the ... ...

Abstract	Abstract Background Randomized controlled trials (RCTs) conducted in the routine care setting provide the opportunity to better understand the effectiveness of new medicines but can present recruitment difficulties. An improved understanding of the challenges/opportunities for patient and healthcare professional (HCP) engagement in clinical research is needed to enhance participation and trial experience. In this study, we explored patient and HCP drivers for, and experiences of, participation in the Salford Lung Studies (SLS), and their views on future trial participation and the overall value of such trials. Methods This was a qualitative study set in Salford, UK, comprising patient telephone interviews (N = 10) and HCP advisory boards (one with general practitioners [GPs], one with practice managers [PMs]); all individuals had participated in the SLS. Semi-structured telephone interviews were recorded, transcribed and analysed thematically. Advisory board meetings were analysed based on transcriptions of audio recordings and field notes. Results For patients, key positive aspects of the SLS were the ease/convenience of study assessments and excellent relationships with study nurses. GPs and PMs considered the SLS to be well-organized and highlighted the value of research nurse support; they also described minor challenges relating to trial systems, initial financial strain on practices and staff turnover. All participants indicated that they were very likely to participate in future trials, citing a design closely aligned with routine care practice as essential. Several strategies to encourage trial participation were suggested, such as clearly communicating benefits to patients and ensuring flexible study assessments. Conclusions Patients and HCPs had positive experiences of the SLS. The study design, closely aligned with routine care, was considered important to their high likelihood of participating in future trials. The experiences of patients and HCPs in the SLS provide valuable insights that will help ...
Keywords	Salford Lung Studies (SLS) ; Effectiveness trial ; Trial experience ; Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: NAVKIDS

van Zwieten, Anita / Ryan, Elizabeth G / Caldwell, Patrina / Howard, Kirsten / Tong, Allison / Craig, Jonathan C / Alexander, Stephen I / Howell, Martin / Teixeira-Pinto, Armando / Hawley, Carmel M / Jesudason, Shilpanjali / Walker, Amanda / Mackie, Fiona / Kennedy, Sean E / McTaggart, Steven / McCarthy, Hugh J / Carter, Simon A / Kim, Siah / Woodleigh, Reginald /

Francis, Anna / Mallard, Alistair R / Bernier-Jean, Amélie / Johnson, David W / Hahn, Deirdre / Reidlinger, Donna / Pascoe, Elaine / Varghese, Julie / Kiriwandeniya, Charani / Vergara, Liza / Larkins, Nicholas / Macauley, Luke / Irving, Michelle / Khalid, Rabia / Guha, Chandana / Wong, Germaine

Trials

2022 Volume 23, Issue 1, Page(s) 824

Abstract: Background: This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS: Methods/design: The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) ... ...

Abstract	Background: This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS Methods/design: The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) prior to the commencement of trial recruitment. During the course of the trial, some key methodological changes needed to be made including changes to eligibility criteria (addition of patients with CKD stages 1-2, broadening of financial status eligibility criterion, addition of patients living in rural/remote areas, modification of age eligibility to 0-16 years, addition of limits related to the language spoken by family, guidance regarding families with multiple eligible children), changes to sites, reduction of sample size, addition of virtual options for consent and study procedures in response to the COVID-19 pandemic, removal of staggered recruitment across sites, addition of outcomes, and changes to the timing and number of assessments. This update summarises the changes made and their rationale and provides the detailed plan for statistical analysis of the trial. These changes have been finalised prior to the completion of study follow-up and the commencement of data analysis. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001152213 . Prospectively registered on 12 July 2018.
MeSH term(s)	Australia ; COVID-19 ; Child ; Humans ; Multicenter Studies as Topic ; Pandemics ; Patient Navigation ; Randomized Controlled Trials as Topic ; Renal Insufficiency, Chronic/diagnosis ; Renal Insufficiency, Chronic/therapy ; SARS-CoV-2 ; Treatment Outcome
Language	English
Publishing date	2022-09-30
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article
ZDB-ID	2040523-6
ISSN	1745-6215 ; 1468-6694 ; 1745-6215
ISSN (online)	1745-6215
ISSN	1468-6694 ; 1745-6215
DOI	10.1186/s13063-022-06783-y
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Article ; Online: Canonical features of human antibodies recognizing the influenza hemagglutinin trimer interface.

The Journal of clinical investigation

2021 Volume 131, Issue 15

Abstract: Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe ...

Abstract	Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of protective human antibodies from several individuals recognizing the trimer interface (TI) of the influenza A HA head, a recently identified site of vulnerability. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody-antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza A HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody-antigen interaction suggests that the TI epitope might serve as an important target for structure-based vaccine design.
MeSH term(s)	Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/chemistry ; Antibodies, Viral/immunology ; Epitopes/chemistry ; Epitopes/immunology ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Humans ; Influenza A Virus, H1N1 Subtype/chemistry ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza Vaccines/chemistry ; Influenza Vaccines/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Hemagglutinin Glycoproteins, Influenza Virus ; Influenza Vaccines
Language	English
Publishing date	2021-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI146791
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