Publications by authors named "David Clarke"

670 Publications

Staged reflexive artificial intelligence driven testing algorithms for early diagnosis of pituitary disorders.

Clin Biochem 2021 Aug 23. Epub 2021 Aug 23.

Division of Endocrinology, Dalhousie University, Halifax, NS Canada. Electronic address:

Background: Sellar masses (SM) frequently present with insidious hormonal dysfunction. We previously showed that, by utilizing a combined reflex/reflecting approach involving a laboratory clinician (LC) on common endocrine test results requested by non-specialists, and subsequently adding further warranted tests, previously undiagnosed pituitary disorders can be identified. However, manually employing these strategies by an LC is not feasible for wider screening of pituitary disorders.

Objective: The aim of this study was to compare the accuracy and financial impact of an Artificial Intelligence (AI) based, fully computerized reflex protocol with manual reflex/reflective intervention protocol led by an LC.

Methods: We developed a proof-of-concept AI-based framework to fully computerize multi-stage reflex testing protocols for pituitary dysfunction using automated reasoning methods. We compared the efficacy of this AI-based protocol with a reflex/reflective protocol based on manually curated retrospective data in identifying pituitary dysfunction based on 12 months of laboratory testing.

Results: The AI-based reflex protocol, as compared with the manual protocol, would have identified laboratory tests for add-on that either directly matched or included all manual add-on tests in 92% of cases, and recommended a similar specialist referral in 90% of the cases. The AI-based protocol would have issued 2.8 times the total number of manual add-on laboratory tests at an 85% lower operation cost than the manual protocol when considering marginal test costs, technical staff and specialist salary.

Conclusion/discussion: Our AI-based reflex protocol can successfully identify patients with pituitary dysfunction, with lower estimated laboratory cost. Future research will focus on enhancing the protocol's accuracy and incorporating the AI-based reflex protocol into institutional laboratory and hospital information systems for the detection of undiagnosed pituitary disorders.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.08.005DOI Listing
August 2021

Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19.

PLoS Pathog 2021 08 23;17(8):e1009865. Epub 2021 Aug 23.

National Biodefense Analysis and Countermeasures Center (NBACC), Operated by Battelle National Biodefense Institute for the US Department of Homeland Security, Frederick, Maryland, United States of America.

While evidence exists supporting the potential for aerosol transmission of SARS-CoV-2, the infectious dose by inhalation remains unknown. In the present study, the probability of infection following inhalation of SARS-CoV-2 was dose-dependent in a nonhuman primate model of inhalational COVID-19. The median infectious dose, assessed by seroconversion, was 52 TCID50 (95% CI: 23-363 TCID50), and was significantly lower than the median dose for fever (256 TCID50, 95% CI: 102-603 TCID50), resulting in a group of animals that developed an immune response post-exposure but did not develop fever or other clinical signs of infection. In a subset of these animals, virus was detected in nasopharyngeal and/or oropharyngeal swabs, suggesting that infected animals without signs of disease are able to shed virus and may be infectious, which is consistent with reports of asymptomatic spread in human cases of COVID-19. These results suggest that differences in exposure dose may be a factor influencing disease presentation in humans, and reinforce the importance of public health measures that limit exposure dose, such as social distancing, masking, and increased ventilation. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, and, ultimately, mitigation strategies. Additionally, these data will be useful to inform dose selection in future studies examining the efficacy of therapeutics and vaccines against inhalational COVID-19, and as a baseline in healthy, young adult animals for assessment of the importance of other factors, such as age, comorbidities, and viral variant, on the infectious dose and disease presentation.
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http://dx.doi.org/10.1371/journal.ppat.1009865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412324PMC
August 2021

Improved identification and quantification of peptides in mass spectrometry data via chemical and random additive noise elimination (CRANE).

Bioinformatics 2021 Jul 29. Epub 2021 Jul 29.

ProCan®, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia.

Motivation: The output of electrospray ionisation - liquid chromatography mass spectrometry (ESI-LC-MS) is influenced by multiple sources of noise and major contributors can be broadly categorised as baseline, random and chemical noise. Noise has a negative impact on the identification and quantification of peptides, which influences the reliability and reproducibility of MS-based proteomics data. Most attempts at denoising have been made on either spectra or chromatograms independently, thus important two-dimensional information is lost because the mass-to-charge ratio and retention time dimensions are not considered jointly.

Results: This paper presents a novel technique for denoising raw ESI-LC-MS data via two-dimensional undecimated wavelet transform, which is applied to proteomics data acquired by data-independent acquisition MS (DIA-MS). We demonstrate that denoising DIA-MS data results in the improvement of peptide identification and quantification in complex biological samples.

Availability: The software is available on Github (https://github.com/CMRI-ProCan/CRANE). The datasets were obtained from ProteomeXchange (Identifiers-PXD002952 and PXD008651). Preliminary data and intermediate files are available via ProteomeXchange (Identifiers-PXD020529 and PXD025103).

Supplementary Information: Supplementary information is available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab563DOI Listing
July 2021

Loss of in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

JCO Precis Oncol 2021 Jun 22;5. Epub 2021 Jun 22.

Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.

Purpose: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition.

Methods: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing.

Results: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for , a key regulator of EMT reprogramming.

Conclusion: We show that EMT characterizes acutely resistant prostate tumors and that deletion of , a key transcriptional regulator of EMT, correlates with clinical response.
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http://dx.doi.org/10.1200/PO.20.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238292PMC
June 2021

A qualitative study of sedentary behaviours in stroke survivors: non-participant observations and interviews with stroke service staff in stroke units and community services.

Disabil Rehabil 2021 Jul 24:1-10. Epub 2021 Jul 24.

Academic Unit for Ageing and Stroke Research, Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, England.

Purpose: Sedentary behaviour (SB) is associated with negative health outcomes and is prevalent post-stroke. This study explored SB after stroke from the perspective of stroke service staff.

Methods: Qualitative mixed-methods study. Non-participant observations in two stroke services (England/Scotland) and semi-structured interviews with staff underpinned by the COM-B model of behaviour change. Observations were analysed thematically; interviews were analysed using the Framework approach.

Results: One hundred and thirty-two observation hours (October - December 2017), and 31 staff interviewed (January -June 2018). Four themes were identified: (1) Opportunities for staff to support stroke survivors to reduce SB; (2) Physical and psychological capability of staff to support stroke survivors to reduce SB; (3) Motivating factors influencing staff behaviour to support stroke survivors to reduce SB; (4) Staff suggestions for a future intervention to support stroke survivors to reduce SB.

Conclusions: Staff are aware of the consequences of prolonged sitting but did not relate to SB. Explicit knowledge of SB was limited. Staff need training to support stroke survivors to reduce SB. Sedentary behaviour in the community was not reported to change markedly, highlighting the need to engage stroke survivors in movement from when capable in hospital, following through to home.Implications for rehabilitationStroke survivor sedentary behaviour is influenced, directly and indirectly, by the actions and instructions of stroke service staff in the inpatient and community setting.The built and social environment, both in the inpatient and community settings, may limit opportunities for safe movement and can result in stroke survivors spending more time sedentary.Stroke service staff appreciate the benefit of encouraging stroke survivors to stand and move more, if it is safe for them to do so.Staff would be amenable to encourage stroke survivors to reduce sedentary behaviour, provided they have the knowledge and resources to equip them to support this.
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http://dx.doi.org/10.1080/09638288.2021.1955307DOI Listing
July 2021

Correction for Clarke et al., "Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics".

Mol Cell Biol 2021 Jul 23;41(8):e0025521. Epub 2021 Jul 23.

Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215.

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http://dx.doi.org/10.1128/MCB.00255-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300775PMC
July 2021

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial.

Lancet Respir Med 2021 Jul 9. Epub 2021 Jul 9.

Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxford, UK.

Background: The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19.

Methods: This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed.

Findings: 298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). No serious adverse events were reported.

Interpretation: In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19.

Funding: National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford and Pfizer.
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http://dx.doi.org/10.1016/S2213-2600(21)00263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270523PMC
July 2021

Author response to: Complications in stereoelectroencephalography: are we too severe?

Acta Neurochir (Wien) 2021 Jun 28. Epub 2021 Jun 28.

Department of Surgery (Division of Neurosurgery), QEII Health Sciences Centre and Dalhousie University, 3844-1796 Summer Street, Halifax, NS, B3H 3A7, Canada.

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http://dx.doi.org/10.1007/s00701-021-04880-6DOI Listing
June 2021

Long-Term Trends in the Epidemiology of Major Traumatic Brain Injury.

J Community Health 2021 Jun 9. Epub 2021 Jun 9.

Division of Neurosurgery, Dalhousie University, QEII Health Sciences Centre, Halifax, Canada.

Traumatic brain injury (TBI) is a leading cause of death and disability among adults. Falls and motor vehicle collisions (MVCs) are the most common causes of TBI hospitalizations in Canada. The purpose of this study was to determine whether, at the provincial level, there have been significant changes in the injury rate and causes of major TBI. This was a retrospective cohort study of all patients in Nova Scotia who presented with major TBI (Abbreviated Injury Scale Head score ≥ 3) between 2002 and 2018. Prospectively entered data were collected from the Nova Scotia Trauma Registry. Annual injury rates were calculated based on 100,000 population (all ages) using population estimates from Statistics Canada. Linear regression was performed to analyze annual trends of major TBI within the province. There were 5590 major TBI patients in Nova Scotia during the 16-year study period. The overall annual rate of major TBI was 37 per 100,000 population. There was a 39% increase in the rate of major TBI over the study period (r =  - 0.72, R2 = 0.51, p < 0.002). Patients had a mean age of 51 ± 25 years; 72% were male. The proportion of TBIs in males decreased significantly from 76% in 2002 to 69% in 2017 (p < 0.001). Mechanisms of injury were predominantly falls (45%) and MVCs (29%); the proportion of violent injuries was 11.5%. The rate of fall-related TBIs more than doubled between 2002 and 2017, increasing from 9.1 to 20.5 injuries per 100,000 (p < 0.001). Our findings demonstrate an increasing incidence of major TBI over a 16-year period with a greater than two-fold increase in the rate of fall-related TBI. These results are important for targeting TBI prevention efforts in reducing falls, especially in older adults.
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http://dx.doi.org/10.1007/s10900-021-01005-zDOI Listing
June 2021

Liver disease prevalence and severity in people with serious mental illness: a cross-sectional analysis using non-invasive diagnostic tools.

Hepatol Int 2021 Jun 3;15(3):812-820. Epub 2021 Jun 3.

Department of Gastroenterology and Hepatology, Monash Health, Level 3, 246 Clayton Road, Clayton, VIC, 3168, Australia.

Background/purpose Of The Study: Little is known about all-cause liver disease in people with serious mental illness (SMI), despite heightened risk factors. We, therefore, prospectively assessed liver disease by etiology and severity in a cross-sectional cohort of people with SMI at a tertiary health service.

Methods: We recruited 255 people with SMI between August 2019 and March 2020. Liver disease data were derived from structured interview, medical records, biochemical and BBV serological analyses, and vibration-controlled transient elastography (VCTE). Steatosis was determined using a threshold of ≥ 248 db/m via the controlled attenuation parameter (CAP) on VCTE. Liver disease prevalence was assessed descriptively, and predictors of metabolic-dysfunction associated fatty liver disease (MAFLD) analyzed using linear regression and multivariable analysis. Best fit modeling of non-invasive screening tests for MAFLD was also assessed.

Results: Valid VCTE was obtained for 252 (98.9%) participants. Median age was 40 years (IQR 31-49) with male predominance (65.9%). Hepatitis C Virus (HCV) seroprevalence was 14.7% (37/252), with four new viremic cases identified. Hepatic steatosis was diagnosed in 61.5% (155/252) of participants, with MAFLD criteria met in 59.9% (151/252) of cases. Clozapine and paliperidone were associated with hepatic steatosis (CAP + 23.3 db/m, p 0.013 and CAP + 25.5, p 0.037, respectively). Advanced liver disease, defined by LSM ≥ 8.2 kPa, was identified in 26 individuals (10.3%). MAFLD compared to no MAFLD was associated with more advanced liver disease (5.3 kPa, 4.3-6.5 versus 4.9 kPa, 3.9-5.6, p < 0.001).

Conclusion: Liver disease is common in people with SMI and should be screened for as part of standard physical health assessment.
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http://dx.doi.org/10.1007/s12072-021-10195-6DOI Listing
June 2021

AUTHENTIC RESEARCH IN THE CLASSROOM INCREASES APPRECIATION FOR PLANTS IN UNDERGRADUATE BIOLOGY STUDENTS.

Integr Comp Biol 2021 May 29. Epub 2021 May 29.

Department of Biology, Appalachian State University, 572 Rivers St, Boone, NC.

Engaging students in authentic research increases student knowledge, develops STEM skills, such as data analysis and scientific communication, and builds community. Creating authentic research opportunities in plant biology might be particularly crucial in addressing plant awareness disparity (formerly known as plant blindness), producing graduates with botanical literacy, and preparing students for plant-focused careers. Our consortium created four CUREs (course-based undergraduate research experiences) focused on dual themes of plant biology and global change, designed to be utilized by early and late-career undergraduates across a variety of educational settings. We implemented these CURES for four semesters, in a total of 15 courses, at four institutions. Pre- and post-course assessments used the Affective Elements of Science Learning Questionnaire and parts of a "plant blindness" instrument to quantify changes in scientific self-efficacy, science values, scientific identity, and plant awareness or knowledge. Qualitative assessment also queried self-efficacy, science values, and scientific identity. Data revealed significant and positive shifts in awareness of and interest in plants across institutions. Quantitative gains in self-efficacy and scientific identity, however, were only found at two of four institutions tested. This project demonstrates that implementing plant CUREs can produce affective and cognitive gains across institutional types and course levels. Focusing on real-world research questions that capture students' imaginations and connect to their sense of place could create plant awareness while anchoring students in scientific identities. While simple interventions can alleviate plant awareness disparity, implementing multiple CUREs per course, or focusing more on final CURE products, could promote larger and more consistent affective gains across institutions.
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http://dx.doi.org/10.1093/icb/icab089DOI Listing
May 2021

Experiences and views of receiving and delivering information about recovery in acquired neurological conditions: a systematic review of qualitative literature.

BMJ Open 2021 04 27;11(4):e045297. Epub 2021 Apr 27.

Academic Unit for Ageing and Stroke Research, University of Leeds, Leeds, UK.

Objective: To review and synthesise qualitative literature relating to the views, perceptions and experiences of patients with acquired neurological conditions and their caregivers about the process of receiving information about recovery; as well as the views and experiences of healthcare professionals involved in delivering this information.

Design: Systematic review of qualitative studies.

Data Sources: MEDLINE, Embase, AMED, CINAHL, PsycINFO, Web of Science and the Cochrane library were searched from their inception to July 2019.

Data Extraction And Synthesis: Two reviewers extracted data from the included studies and assessed quality using an established tool. Thematic synthesis was used to synthesise the findings of included studies.

Results: Searches yielded 9105 titles, with 145 retained for full-text screening. Twenty-eight studies (30 papers) from eight countries were included. Inductive analysis resulted in 11 descriptive themes, from which 5 analytical themes were generated: the right information at the right time; managing expectations; it's not what you say, it's how you say it; learning how to talk about recovery and manage emotions; the context of uncertainty.

Conclusions: Our findings highlight the inherent challenges in talking about recovery in an emotional context, where breaking bad news is a key feature. Future interventions should focus on preparing staff to meet patients' and families' information needs, as well as ensuring they have the skills to discuss potential recovery and break bad news compassionately and share the uncertain trajectory characteristic of acquired neurological conditions. An agreed team-based approach to talking about recovery is recommended to ensure consistency and improve the experiences of patients and their families.
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http://dx.doi.org/10.1136/bmjopen-2020-045297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088240PMC
April 2021

Host-Guest Induced Peptide Folding with Sequence-Specific Structural Chirality.

J Am Chem Soc 2021 May 16;143(17):6323-6327. Epub 2021 Apr 16.

Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.

Controlling the spatial and temporal behavior of peptide segments is essential in the fabrication of functional peptide-based materials and nanostructures. To achieve a desired structure, complex sequence design is often required, coupled with the inclusion of unnatural amino acids or synthetic modifications. Herein, we investigate the structural properties of 1:1 inclusion complexes between specific oligopeptides and cucurbit[8]uril (CB[8]), inducing the formation of turns, and by alteration of the peptide sequence, tunable structural chirality. We also explore extended peptide sequence binding with CB[8], demonstrating a simple approach to construct a peptide hairpin.
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http://dx.doi.org/10.1021/jacs.1c00342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154536PMC
May 2021

Concussion in para sport: the first position statement of the Concussion in Para Sport (CIPS) Group.

Br J Sports Med 2021 Apr 9. Epub 2021 Apr 9.

Para Football Foundation, Arnhem, The Netherlands.

Concussion is a frequent injury in many sports and is also common in para athletes. However, there is a paucity of concussion research related to para sport, and prior International Concussion in Sport (CIS) consensus papers have not substantively addressed this population. To remedy this and to improve concussion care provided to para athletes, the concussion in para sport (CIPS) multidisciplinary expert group was created. This group analysed and discussed in-depth para athlete-specific issues within the established key clinical domains of the current (2017) consensus statement on CIS. Due to the onset of the COVID-19 pandemic, the group held all meetings by video conferencing. The existing Sport Concussion Assessment Tool 5 (SCAT5) for the immediate on-field and office-based off-field assessment of concussion was evaluated as part of this process, to identify any para athlete-specific concerns. Regular preparticipation and periodic health examinations are essential to determine a baseline reference point for concussion symptoms but pose additional challenges for the interpreting clinician. Further considerations for concussion management for the para athlete are required within the remove, rest, reconsider and refer consensus statement framework. Considering return to sport (RTS), the 2017 CIS consensus statement has limitations when considering the RTS of the para athlete. Case-by-case decision making related to RTS following concussion is imperative for para athletes. Additional challenges exist for the evaluation and management of concussion in para athletes. There is a need for greater understanding of existing knowledge gaps and attitudes towards concussion among athlete medical staff, coaches and para athletes. Future research should investigate the use and performance of common assessment tools in the para athlete population to better guide their clinical application and inform potential modifications. Concussion prevention strategies and sport-specific rule changes, such as in Para Alpine Skiing and Cerebral Palsy Football, also should be carefully considered to reduce the occurrence of concussion in para athletes.
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http://dx.doi.org/10.1136/bjsports-2020-103696DOI Listing
April 2021

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.

Cell Rep 2021 Mar;34(12):108862

University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gα protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gα, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy.
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http://dx.doi.org/10.1016/j.celrep.2021.108862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994375PMC
March 2021

Preclinical Evaluation of the Stealth Autoguide Robotic Guidance Device for Stereotactic Cranial Surgery: A Human Cadaveric Study.

Stereotact Funct Neurosurg 2021 10;99(4):343-350. Epub 2021 Feb 10.

Department of Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada,

Introduction: Stereotactic procedures are routinely performed for brain biopsies, deep brain stimulation, and placement of stereoelectroencephalography (SEEG) electrodes for epilepsy. The recently developed Stealth Autoguide (Medtronic, Minneapolis, MN, USA) device does not require patients to don a stereotactic frame. In this preclinical study, we sought to quantitatively compare the Stealth Autoguide robotic system to 2 devices commonly used in clinical practice: the Navigus biopsy system (Medtronic) and the Leksell stereotactic frame (Elekta Ltd., Stockholm, Sweden).

Methods: In the first experimental setup, we compared target accuracy of the Stealth Autoguide to the Navigus system by using phantom heads filled with gelatin to simulate the brain tissue. In the second experimental setup, we inserted SEEG electrodes to targets within cadaveric heads in a simulated operating room environment.

Results: Using a homogeneous gelatin-filled phantom 3D reconstruction of a human head, we found that using the Stealth Autoguide system, while maintaining accuracy, was faster to use than the Navigus system. In our simulated operating room environment using nonliving human cadaveric heads, we found the accuracy of the Stealth Autoguide robotic device to be comparable to that of the Leksell frame.

Discussion/conclusion: These results compare the use of the Stealth Autoguide robotic guidance system with commonly used stereotactic devices, and this is the first study to compare its use and accuracy with the Leksell frame. These findings provide mounting evidence that Stealth Autoguide will have potential clinical uses in various stereotactic neurosurgical procedures.
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http://dx.doi.org/10.1159/000512508DOI Listing
February 2021

Co-designing organisational improvements and interventions to increase inpatient activity in four stroke units in England: a mixed-methods process evaluation using normalisation process theory.

BMJ Open 2021 01 26;11(1):e042723. Epub 2021 Jan 26.

Faculty of Health Social Care and Education, St Georges University of London, London, UK.

Objective: To explore facilitators and barriers to using experience-based co-design (EBCD) and accelerated EBCD (AEBCD) in the development and implementation of interventions to increase activity opportunities for inpatient stroke survivors.

Design: Mixed-methods process evaluation underpinned by normalisation process theory (NPT).

Setting: Four post-acute rehabilitation stroke units in England.

Participants: Stroke survivors, family members, stroke unit staff, hospital managers, support staff and volunteers. Data informing our NPT analysis comprised: ethnographic observations, n=366 hours; semistructured interviews with 76 staff, 53 stroke survivors and 27 family members pre-EBCD/AEBCD implementation or post-EBCD/AEBCD implementation; and observation of 43 co-design meetings involving 23 stroke survivors, 21 family carers and 54 staff.

Results: Former patients and families valued participation in EBCD/AEBCD perceiving they were equal partners in co-design. Staff engaged with EBCD/AEBCD, reporting it as a valuable improvement approach leading to increased activity opportunities. The structured EBCD/AEBCD approach was influential in enabling coherence and cognitive participation and legitimated staff involvement in the change process. Researcher facilitation of EBCD/AEBCD supported cognitive participation, collective action and reflexive monitoring; these were important in implementing and sustaining co-design activities. Observations and interviews post-EBCD/AEBCD cycles confirmed creation and use of new social spaces and increased activity opportunities in all units. EBCD/AEBCD facilitated engagement with wider hospital resources and local communities, further enhancing activity opportunities. However, outside of structured group activity, many individual staff-patient interactions remained task focused.

Conclusions: EBCD/AEBCD facilitated the development and implementation of environmental changes and revisions to work routines which supported increased activity opportunities in stroke units providing post-acute and rehabilitation care. Former stroke patients and carers contributed to improvements. NPT's generative mechanisms were instrumental in analysis and interpretation of facilitators and barriers at the individual, group and organisational level, and can help inform future implementations of similar approaches.
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http://dx.doi.org/10.1136/bmjopen-2020-042723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839845PMC
January 2021

Intraosseous Cavernous Hemangioma of the Middle Turbinate: A Case Report.

Ear Nose Throat J 2021 Jan 19:145561320984581. Epub 2021 Jan 19.

Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: We report a case of an intraosseous cavernous hemangioma originating from the middle turbinate that expanded into the anterior skull base, without traversing the cribriform plate.

Methods: The mass was found incidentally after a computed tomography head was ordered for unrelated reasons. On questioning, the patient denied any nasal symptoms. Magnetic resonance imaging showed an enhancing mass and the radiological imaging supported a broad differential.

Results: The lesion was removed by endoscopic image-guided surgery, and the pathology was that of a benign intraosseous cavernous hemangioma. There was no residual hemangioma on postoperative imaging and the nasal mucosa healed well. This is the first report of an intraosseous cavernous hemangioma of the middle turbinate showing superior expansion to the anterior skull base.

Conclusion: This case demonstrates the extent to which cavernous hemangiomas may expand into surrounding tissues. While these lesions are uncommon, they can be considered as part of a broad differential diagnosis of sinonasal tumors.
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http://dx.doi.org/10.1177/0145561320984581DOI Listing
January 2021

Behavior Sequencing Violent Episodes in Forensic Youth Populations.

Int J Offender Ther Comp Criminol 2021 Jan 19:306624X21988991. Epub 2021 Jan 19.

Researchers in Behaviour Sequence Analysis (ReBSA).

Every year, more children and youths are sent to Secure Children's Homes while moving through the criminal justice system. Aggressive and violent incidents in these settings are common, and staff are often required to intervene and restrain violent individuals. The research literature has many examples of aggression and violence questionnaires and measures; however, for staff in communal areas it is the observable behaviors that they react to most. The current research, therefore, analyzed observable behaviors leading-up to violent episodes, and used Behavior Sequence Analysis to highlight the typical chains of behaviors that tend toward violence. The outcomes of this research show pathways to violence that staff can use to highlight potential spirals of aggression and violence. The current results show the links between non-confrontational behaviors (e.g., talking) through to more confrontational (staring, approaching, and pushing others). Overall, the research forms the foundation for future investigation into these and similar settings and outlines a novel approach to understanding violence escalation in a way that can be interpreted and used by service staff.
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http://dx.doi.org/10.1177/0306624X21988991DOI Listing
January 2021

Validation of 3D fluoroscopy for image-guidance registration in depth electrode implantation for medically refractory epilepsy.

Acta Neurochir (Wien) 2021 05 14;163(5):1347-1354. Epub 2021 Jan 14.

Department of Surgery, Division of Neurosurgery, QEII Health Sciences Centre and Dalhousie University, 1796 Summer Street, Halifax, NS, Canada.

Background: Frame registration is a critical step to ensure accurate electrode placement in stereotactic procedures such as stereoelectroencephalography (SEEG) and is routinely done by merging a computed tomography (CT) scan with the preoperative magnetic resonance (MR) examination. Three-dimensional fluoroscopy (XT) has emerged as a method for intraoperative electrode verification following electrode implantation and more recently has been proposed as a registration method with several advantages.

Methods: We compared the accuracy of SEEG electrode placement by frame registration with CT and XT imaging by analyzing the Euclidean distance between planned and post-implantation trajectories of the SEEG electrodes to calculate the error in both the entry (EP) and target (TP) points. Other variables included radiation dose, efficiency, and complications.

Results: Twenty-seven patients (13 CT and 14 XT) underwent placement of SEEG electrodes (319 in total). The mean EP and TP errors for the CT group were 2.3 mm and 3.3 mm, respectively, and 1.9 mm and 2.9 mm for the XT group, with no statistical difference (p = 0.75 and p = 0.246). The time to first electrode placement was similar (XT, 82 ± 10 min; CT, 84 ± 22 min; p = 0.858) and the average radiation exposure with XT (234 ± 55 mGy*cm) was significantly lower than CT (1245 ± 123 mGy*cm) (p < 0.0001). Four complications were documented with equal incidence in both groups.

Conclusions: The use of XT as a method for registration resulted in similar implantation accuracy compared with CT. Advantages of XT are the substantial reduction in radiation dose and the elimination of the need to transfer the patient out of the room which may have an impact on patient safety and OR efficiency.
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http://dx.doi.org/10.1007/s00701-021-04706-5DOI Listing
May 2021

Doing nothing? An ethnography of patients' (In)activity on an acute stroke unit.

Health (London) 2021 Jan 9:1363459320969784. Epub 2021 Jan 9.

Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care, King's College London, UK.

Health research has begun to pay increasing attention to inactivity in its broadest sense as lack of meaningful activity and boredom. Few studies however have taken a critical look at this phenomenon. We explore (in)activity drawing on ethnographic data from observations in an acute stroke unit and post-discharge interviews with stroke survivors and their families. Four themes emerged that explain patients' (in)activity: (i) planned activities; (ii) 'doing nothing', (iii) the material environment of the unit; (iv) interactions with staff. Considering these themes, we seek to problematise received conceptual and methodological approaches to understanding (in)activity. We argue that (in)activity is best conceived not as lack of action or meaning, but as a situated practice encompassing both bodily and mental activities that reflect and reproduce the way in which life is collectively organised within a specific healthcare setting.
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http://dx.doi.org/10.1177/1363459320969784DOI Listing
January 2021

Design and implementation of electronic health record common data elements for pediatric epilepsy: Foundations for a learning health care system.

Epilepsia 2021 01 24;62(1):198-216. Epub 2020 Dec 24.

Department of Neurology, St Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Objective: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy.

Methods: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types.

Results: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center.

Significance: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy.
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http://dx.doi.org/10.1111/epi.16733DOI Listing
January 2021

An Unusual Todd's Phenomenon: Post-Ictal Prosopagnosia.

Can J Neurol Sci 2021 Sep 4;48(5):730-731. Epub 2020 Dec 4.

Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.

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http://dx.doi.org/10.1017/cjn.2020.264DOI Listing
September 2021

Microbial Polyethylene Terephthalate Hydrolases: Current and Future Perspectives.

Front Microbiol 2020 11;11:571265. Epub 2020 Nov 11.

School of Microbiology, University College Cork, Cork, Ireland.

Plastic has rapidly transformed our world, with many aspects of human life now relying on a variety of plastic materials. Biological plastic degradation, which employs microorganisms and their degradative enzymes, has emerged as one way to address the unforeseen consequences of the waste streams that have resulted from mass plastic production. The focus of this review is microbial hydrolase enzymes which have been found to act on polyethylene terephthalate (PET) plastic. The best characterized examples are discussed together with the use of genomic and protein engineering technologies to obtain PET hydrolase enzymes for different applications. In addition, the obstacles which are currently limiting the development of efficient PET bioprocessing are presented. By continuing to study the possible mechanisms and the structural elements of key enzymes involved in microbial PET hydrolysis, and by assessing the ability of PET hydrolase enzymes to work under practical conditions, this research will help inform large-scale waste management operations. Finally, the contribution of microbial PET hydrolases in creating a potential circular PET economy will be explored. This review combines the current knowledge on enzymatic PET processing with proposed strategies for optimization and use, to help clarify the next steps in addressing pollution by PET and other plastics.
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http://dx.doi.org/10.3389/fmicb.2020.571265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686037PMC
November 2020

Addressing inactivity after stroke: The Collaborative Rehabilitation in Acute Stroke (CREATE) study.

Int J Stroke 2021 08 2;16(6):669-682. Epub 2020 Nov 2.

Leeds Institute of Health Sciences, University of Leeds, Leeds, UK.

Background: Stroke patients are often inactive outside of structured therapy sessions - an enduring international challenge despite large scale organizational changes, national guidelines and performance targets. We examined whether experienced-based co-design (EBCD) - an improvement methodology - could address inactivity in stroke units.

Aims: To evaluate the feasibility and impact of patients, carers, and staff co-designing and implementing improvements to increase supervised and independent therapeutic patient activity in stroke units and to compare use of full and accelerated EBCD cycles.

Methods: Mixed-methods case comparison in four stroke units in England.

Results: Interviews were held with 156 patients, staff, and carers in total; ethnographic observations for 364 hours, behavioral mapping of 68 patients, and self-report surveys from 179 patients, pre- and post-implementation of EBCD improvement cycles.Three priority areas emerged: (1) 'Space' (environment); (2) 'Activity opportunities' and (3) 'Communication'. More than 40 improvements were co-designed and implemented to address these priorities across participating units. Post-implementation interview and ethnographic observational data confirmed use of new social spaces and increased activity opportunities. However, staff interactions remained largely task-driven with limited focus on enabling patient activity. Behavioral mapping indicated some increases in social, cognitive, and physical activity post-implementation, but was variable across sites. Survey responses rates were low at 12-38% and inconclusive.

Conclusion: It was feasible to implement EBCD in stroke units. This resulted in multiple improvements in stroke unit environments and increased activity opportunities but minimal change in recorded activity levels. There was no discernible difference in experience or outcome between full and accelerated EBCD; this methodology could be used across hospital stroke units to assist staff and other stakeholders to co-design and implement improvement plans.
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http://dx.doi.org/10.1177/1747493020969367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366168PMC
August 2021

In-Hospital Endocrinology Consultation After Transsphenoidal Surgery: Is It Always Necessary?

Can J Neurol Sci 2021 07 16;48(4):534-539. Epub 2020 Oct 16.

Division of Neurosurgery, Dalhousie University, Halifax, NS, Canada.

Background: Patients with sellar masses undergoing transsphenoidal surgery (TSS) frequently develop endocrine dysfunction; therefore, in-hospital endocrinology consultation (IHEC) is recommended. However, we wondered whether routine endocrinology assessment of all TSS patients is always necessary.

Methods: We developed an IHEC Physician's Guide to identify patients who would require peri-operative IHEC. An analysis of all patients undergoing TSS for a sellar mass over a 4-year period was conducted to assess the predictive value of the IHEC Physician's Guide in identifying patients who required IHEC.

Results: A total of 116 patients underwent TSS; 24 required IHEC. As expected, the risk of endocrine complications requiring peri-operative endocrine management was significantly higher in the IHEC group versus no-IHEC group (96% vs. 1%; p < 0.001). The negative predictive value of the IHEC Physician's Guide in identifying patients who did not require IHEC was 0.99 (95% CI 0.9409-0.9997); Fisher's exact test, p < 0.001), meaning that the IHEC Physician's Guide successfully identified all but one patient who truly required IHEC.

Conclusion: Results from our study show that most patients do not need IHEC after TSS and that those patients requiring IHEC can be reliably predicted at surgery by using a simple IHEC Physician's Guide.
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http://dx.doi.org/10.1017/cjn.2020.226DOI Listing
July 2021

Evaluation of Rat Acute Phase Proteins as Inflammatory Biomarkers for Vaccine Nonclinical Safety Studies.

Toxicol Pathol 2020 10 12;48(7):845-856. Epub 2020 Oct 12.

105623Pfizer Inc, Worldwide Research Development and Medical, Drug Safety Research and Development, Pearl River, NY, USA.

The objectives were to characterize the kinetics of acute phase proteins (APPs) α-2 macroglobulin (A2M), α-1 acid glycoprotein (A1AGP), and fibrinogen (FIB), and injection site macroscopic and microscopic findings following intramuscular administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (TDaP; Adacel); adjuvants (aluminum phosphate [AlPO]; aluminum hydroxide, Al[OH]; CpG/Al[OH]; or Quillaja saponaria 21 [QS-21]); or saline to female Wistar Han rats. Intravascular lipopolysaccharide (LPS) was a positive control. Injection sites and lymph nodes were evaluated microscopically, using hematoxylin and eosin (H&E) stained sections, 48 hours postdose (HPD) and compared with APP concentrations; A2M and A1AGP were measured using Meso Scale Discovery analyzer. Fibrinogen was measured on STA Compact analyzer. In a time-course study, APP peaked at 24 or 48 HPD. In a subsequent study at 48 HPD, injection site microscopic changes included inflammation and muscle degeneration/necrosis, which was different in severity/nature between groups. The APPs were not increased in rats administered saline, Al(OH), or AlPO. Fibrinogen and A1AGP increased in rats administered CpG/Al(OH), QS-21, or TDaP; and A2M increased in rats administered QS-21. Fibrinogen, A2M, and A1AGP increased after LPS administration. Acute phase proteins can be used to monitor inflammatory responses to adjuvants; however, some adjuvants may induce inflammation without higher APPs.
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http://dx.doi.org/10.1177/0192623320957281DOI Listing
October 2020

Strict conformational demands of RNA cleavage in bulge-loops created by peptidyl-oligonucleotide conjugates.

Nucleic Acids Res 2020 11;48(19):10662-10679

School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Potent knockdown of pathogenic RNA in vivo is an urgent health need unmet by both small-molecule and biologic drugs. 'Smart' supramolecular assembly of catalysts offers precise recognition and potent destruction of targeted RNA, hitherto not found in nature. Peptidyl-oligonucleotide ribonucleases are here chemically engineered to create and attack bulge-loop regions upon hybridization to target RNA. Catalytic peptide was incorporated either via a centrally modified nucleotide (Type 1) or through an abasic sugar residue (Type 2) within the RNA-recognition motif to reveal striking differences in biological performance and strict structural demands of ribonuclease activity. None of the Type 1 conjugates were catalytically active, whereas all Type 2 conjugates cleaved RNA target in a sequence-specific manner, with up to 90% cleavage from 5-nt bulge-loops (BC5-α and BC5L-β anomers) through multiple cuts, including in folds nearby. Molecular dynamics simulations provided structural explanation of accessibility of the RNA cleavage sites to the peptide with adoption of an 'in-line' attack conformation for catalysis. Hybridization assays and enzymatic probing with RNases illuminated how RNA binding specificity and dissociation after cleavage can be balanced to permit turnover of the catalytic reaction. This is an essential requirement for inactivation of multiple copies of disease-associated RNA and therapeutic efficacy.
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http://dx.doi.org/10.1093/nar/gkaa780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641753PMC
November 2020
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