Publications by authors named "Aaron Wong"

182 Publications

Telehealth in outpatient delivery of palliative care: A qualitative study of patient and physician views.

Palliat Support Care 2022 Jul 12:1-8. Epub 2022 Jul 12.

Parkville Integrated Palliative Care Service, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Objectives: The COVID-19 pandemic has widened the funded use of telehealth in Australia to support telehealth delivery to all patients in any setting. Increasing the use and experience of telehealth brings to light unique insights into the advantages and challenges of this new model of healthcare delivery This study aimed to qualitatively explore the experiences of both palliative care physicians and patients setting, including their views on its future role in healthcare.

Methods: This qualitative study was conducted across three metropolitan tertiary palliative care centers in Victoria, Australia between November 2020 and March 2021. Purposive sampling identified 23 participants (12 physicians and 11 patients). Semi-structured interviews focused on the last telehealth consultation, thoughts and impressions of telehealth, and the possibility of telehealth remaining in palliative care. A thematic approach was adopted to code and analyze the data.

Results: Telehealth transformed the ways physicians and patients in this study perceived and engaged with outpatient palliative care across the entire continuum of care. Four key themes were identified: (1) access to care; (2) delivery of care; (3) engagement with care; and (4) the future.

Significance Of Results: This study provides novel data bringing together the perspective of patients and physicians, which confirms the utility of telehealth in palliative care. Its convenience enables more frequent review, enables reviews to occur in response to lower levels of concern, and adds toward enhancing the continuity of care across and between settings. Moving forward, support seemed strongest for a hybrid model of telehealth and face-to-face consultations guided by key parameters relating to the level of anticipated complexity.
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http://dx.doi.org/10.1017/S1478951522000670DOI Listing
July 2022

A sequence-based global map of regulatory activity for deciphering human genetics.

Nat Genet 2022 Jul 11;54(7):940-949. Epub 2022 Jul 11.

Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease.
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http://dx.doi.org/10.1038/s41588-022-01102-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279145PMC
July 2022

Microbial isolates with Anti-Pseudogymnoascus destructans activities from Western Canadian bat wings.

Sci Rep 2022 06 14;12(1):9895. Epub 2022 Jun 14.

Department of Biological Sciences, Faculty of Science, Thompson Rivers University, Kamloops, BC, V2C 08C, Canada.

Pseudogymnoascus destructans (Pd) is the causative agent of white-nose syndrome, which has resulted in the death of millions of bats in North America (NA) since 2006. Based on mortalities in eastern NA, the westward spread of infections likely poses a significant threat to western NA bats. To help prevent/reduce Pd infections in bats in western NA, we isolated bacteria from the wings of wild bats and screened for inhibitory activity against Pd. In total, we obtained 1,362 bacterial isolates from 265 wild bats of 13 species in western Canada. Among the 1,362 isolates, 96 showed inhibitory activity against Pd based on a coculture assay. The inhibitory activities varied widely among these isolates, ranging from slowing fungal growth to complete inhibition. Interestingly, host bats containing isolates with anti-Pd activities were widely distributed, with no apparent geographic or species-specific pattern. However, characteristics of roosting sites and host demography showed significant associations with the isolation of anti-Pd bacteria. Specifically, anthropogenic roosts and swabs from young males had higher frequencies of anti-Pd bacteria than those from natural roosts and those from other sex and age-groups, respectively. These anti-Pd bacteria could be potentially used to help mitigate the impact of WNS. Field trials using these as well as additional microbes from future screenings are needed in order to determine their effectiveness for the prevention and treatment against WNS.
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http://dx.doi.org/10.1038/s41598-022-14223-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198084PMC
June 2022

A Multi-Centre COVID-19 Study Examining Symptoms and Medication Use in the Final Week of Life.

J Pain Symptom Manage 2022 Sep 26;64(3):e139-e147. Epub 2022 May 26.

Parkville Integrated Palliative Care Service (A.K.W., J.P., R.E., J.C., B.L.) Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Context: Guidelines exist to direct end-of-life symptom management in COVID-19 patients. However, the real-world symptom patterns, and degree of concordance with guidelines on medication use, and palliative care involvement has received limited attention.

Objectives: To describe the evolution of COVID-19 symptoms, medication used to alleviate these, and degree of palliative care involvement in the final week of life.

Methods: This retrospective study reviewed all COVID-19 inpatient deaths across five metropolitan hospitals in Australia from January 1 to December 31, 2020. Outcome measures were collected at day of death, and days one, two, five and seven before death. These were COVID-19 symptom severity (measured by the Palliative Care Outcome Scale), and use of supportive pharmacological and non-pharmacological therapies. Palliative care referral timepoint was also collected.

Results: Within the sample of 230 patients, commonest symptoms were breathlessness, agitation, pain, and respiratory secretions. On day of death, 79% (n = 181) experienced at least one symptom, and 30% (n = 68) experienced severe/extreme symptoms. The use of midazolam, glycopyrrolate, and infusions for symptom management occurred late, less frequently, and at lower doses than suggested in guidelines and other studies. Palliative care referrals were made late, at median three days before death (IQR 1-6 days), and for only half of people dying from COVID-19 (51%; n = 118).

Conclusion: Symptoms peaked in final three days of life. Earlier use of in fusional and breakthrough medications should be considered in anticipation of symptoms given high likelihood of dying in discomfort. Earlier palliative care referral for high-risk patients should be considered at hospital admission.
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http://dx.doi.org/10.1016/j.jpainsymman.2022.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134756PMC
September 2022

Viability and Cosmesis of Right Angle and Vertical Paramedian Forehead Flaps Are Equivalent: A Retrospective Quantitative Study.

Dermatol Surg 2022 Jul 16;48(7):716-719. Epub 2022 May 16.

All authors are affiliated with the Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada.

Background: Paramedian forehead flaps (PMFFs) are commonly used for reconstruction of nasal defects. The classic PMFF is vertically oriented while the modified PMFF is designed with a 90-degree angle. No study has compared outcomes between these PMFF designs.

Objective: To compare and quantify viability and cosmesis of 90-degree and vertical PMFF.

Methods: Retrospective chart review of 70 consecutive patients with a vertical or 90-degree PMFF design for nasal repairs after Mohs micrographic surgery (MMS). Cosmetic outcome was assessed on a 10-cm, 100-point, visual analog scale (VAS) by an independent observer using standardized 3-month postoperative photographs. Flap viability was assessed using standardized 3-week postoperative photographs. Descriptive statistics, t -test, and Mann-Whitney test were used for statistical analysis.

Results: Forty-eight patients were repaired with a vertical PMFF and 22 using the 90-degree PMFF. The mean defect area of vertical and 90-degree designs was equivalent (7.7 ± 4.0 cm 2 vs 8.1 ± 4.0 cm 2 , p = .70). There was no significant difference in cosmetic outcome (75.9 ± 9.4 vs 72.9 ± 6.8, p = .19) or flap viability (3.8% ± 11.6 vs 2.6% ± 7.9, p = .67) between vertical and 90-degree designs.

Conclusion: Vertical and 90-degree PMFF designs for nasal repairs after MMS are equivalent in cosmetic outcome and viability.
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http://dx.doi.org/10.1097/DSS.0000000000003476DOI Listing
July 2022

Molecular Characterization of Membranous Nephropathy.

J Am Soc Nephrol 2022 06 27;33(6):1208-1221. Epub 2022 Apr 27.

Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts

Background: Molecular characterization of nephropathies may facilitate pathophysiologic insight, development of targeted therapeutics, and transcriptome-based disease classification. Although membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome, the molecular pathways of kidney damage in MN require further definition.

Methods: We applied a machine-learning framework to predict diagnosis on the basis of gene expression from the microdissected kidney tissue of participants in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We sought to identify differentially expressed genes between participants with MN versus those of other glomerulonephropathies across the NEPTUNE and European Renal cDNA Bank (ERCB) cohorts, to find MN-specific gene modules in a kidney-specific functional network, and to identify cell-type specificity of MN-specific genes using single-cell sequencing data from reference nephrectomy tissue.

Results: Glomerular gene expression alone accurately separated participants with MN from those with other nephrotic syndrome etiologies. The top predictive classifier genes from NEPTUNE participants were also differentially expressed in the ERCB participants with MN. We identified a signature of 158 genes that are significantly differentially expressed in MN across both cohorts, finding 120 of these in a validation cohort. This signature is enriched in targets of transcription factor NF-κB. Clustering these MN-specific genes in a kidney-specific functional network uncovered modules with functional enrichments, including in ion transport, cell projection morphogenesis, regulation of adhesion, and wounding response. Expression data from reference nephrectomy tissue indicated 43% of these genes are most highly expressed by podocytes.

Conclusions: These results suggest that, relative to other glomerulonephropathies, MN has a distinctive molecular signature that includes upregulation of many podocyte-expressed genes, provides a molecular snapshot of MN, and facilitates insight into MN's underlying pathophysiology.
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http://dx.doi.org/10.1681/ASN.2021060784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161788PMC
June 2022

A multi-centre study on patients dying from COVID-19: Communication Between Clinicians, Patients, and their Families.

Intern Med J 2022 Apr 26. Epub 2022 Apr 26.

Department of Medicine, University of Melbourne, Eastern Hill Campus, Victoria Parade, Fitzroy, Victoria, Australia, 3065.

Background: COVID-19 has led to challenges in providing effective and timely communication in healthcare. Services have been required to adapt and evolve as successful communication remains core to high quality patient-centred care.

Aim: This study aims to describe the communication between admitted patients, their families and clinicians (medical, nursing, allied health) during end-of-life care.

Methods: This retrospective review included all patients (n = 230) who died directly due to COVID-19 at five Melbourne hospitals between 1 January and 31 December 2020. Contacts and modality used (face to face, video, telephone) during the 8 days prior to death were recorded.

Results: Patients were predominantly elderly (median age 86 years) and from residential aged care facilities (62% (n = 141)). Communication frequency increased the closer the patient was to death, where on day of death, contact between clinicians and patients was 93% (n = 213) clinicians and families 97%(n = 222) and between patients and families 50% (n = 115). Most contact between patients and families was facilitated by a clinician (91.3% (n = 105) day of death) with the most commonly used mode being video call (n = 30 day of death).

Conclusion: This study is one of the first and largest Australian reports on how communication occurs at the end of life for patients dying of COVID-19. Contact rates were relatively low between patients and families, compared to other cohorts dying from non COVID-19 related causes. The impact of this difference on bereavement outcomes requires surveillance and attention. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9111806PMC
April 2022

Action imitation via trajectory-based or posture-based planning.

Hum Mov Sci 2022 Jun 20;83:102951. Epub 2022 Apr 20.

Moss Rehabilitation Research Institute, 60 Township Line Rd, Elkins Park, PA 19027, USA.

Imitation is a significant daily activity involved in social interaction and motor learning. Imitation has been theorized to be performed in at least two ways. In posture-based imitation, individuals reproduce how the body should look and feel, and are sensitive to the relative positioning of body parts. In trajectory imitation, individuals mimic the spatiotemporal motion path of the end effector. There are clear anecdotal situations in which one might benefit from imitating postures (when learning ballet) or trajectories (when learning to reach around objects). However, whether these are in fact distinct methods of imitation, and if so, whether they may be applied interchangeably to perform the same task, remain unknown. If these are indeed separate mechanisms that rely on different computational and neural resources, a cost should be incurred when switching from using one mechanism to the other within the context of a single task. Therefore, observing a processing cost would both provide evidence that these are indeed two distinct mechanisms, and that they may be used interchangeably when trying to imitate the same stimulus. To test this, twenty-five healthy young adults performed a sequential multitasking imitation task. Participants were first instructed to pay attention to the limb postures or the hand path of a video-recorded model, then performed a neutral, congruent, or incongruent intervening motor task. Finally, participants imitated the modeled movement. We examined both spatial and temporal imitation accuracy as well as individual spatial consistency. When the primary task involved imitating trajectories, analysis of individual consistency suggested a processing cost: movements following the posture-matching intervening task were less consistent with baseline (neutral) performance, suggesting performance may be disrupted by the incongruence. This effect was not observed when imitating limb postures. In summary, we present initial evidence for a difference between posture matching and trajectory imitation as a result of instructions and intervening tasks that is consistent with the existence of two computationally distinct imitation mechanisms.
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http://dx.doi.org/10.1016/j.humov.2022.102951DOI Listing
June 2022

BMP1 is not required for lung fibrosis in mice.

Sci Rep 2022 03 31;12(1):5466. Epub 2022 Mar 31.

Department of Discovery Immunology, Genentech, South San Francisco, CA, USA.

Bone morphogenetic protein 1 (BMP1) belongs to the astacin/BMP1/tolloid-like family of zinc metalloproteinases, which play a fundamental role in the development and formation of extracellular matrix (ECM). BMP1 mediates the cleavage of carboxyl terminal (C-term) propeptides from procollagens, a crucial step in fibrillar collagen fiber formation. Blocking BMP1 by small molecule or antibody inhibitors has been linked to anti-fibrotic activity in the preclinical models of skin, kidney and liver fibrosis. Therefore, we reason that BMP1 may be important for the pathogenesis of lung fibrosis and BMP1 could be a potential therapeutic target for progressive fibrotic disease such as idiopathic pulmonary fibrosis (IPF). Here, we observed the increased expression of BMP1 in both human IPF lungs and mouse fibrotic lungs induced by bleomycin. Furthermore, we developed an inducible Bmp1 conditional knockout (cKO) mouse strain. We found that Bmp1 deletion does not protect mice from lung fibrosis triggered by bleomycin. Moreover, we found no significant impact of BMP1 deficiency upon C-term propeptide of type I procollagen (CICP) production in the fibrotic mouse lungs. Based on these results, we propose that BMP1 is not required for lung fibrosis in mice and BMP1 may not be considered a candidate therapeutic target for IPF.
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http://dx.doi.org/10.1038/s41598-022-09557-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971496PMC
March 2022

Motor Plans under Uncertainty Reflect a Trade-Off between Maximizing Reward and Success.

eNeuro 2022 Mar-Apr;9(2). Epub 2022 Apr 12.

Moss Rehabilitation Research Institute, Elkins Park, PA 19027.

When faced with multiple potential movement options, individuals either reach directly to one of the options, or initiate a reach intermediate between the options. It remains unclear why people generate these two types of behaviors. Using the go-before-you-know task (commonly used to study behavior under choice uncertainty) in humans, we examined two key questions. First, do these two types of responses actually reflect distinct movement strategies? If so, the relative desirability (i.e., weighing the success likelihood vs the attainable reward) of the two target options would not need to be computed identically for direct and intermediate reaches. We showed that indeed, when reward and success likelihood differed between the two options, reach direction was preferentially biased toward different directions for direct versus intermediate reaches. Importantly, this suggests that the computation of subjective values depends on the choice of movement strategy. Second, what drives individual differences in how people respond under uncertainty? We found that risk/reward-seeking individuals tended to generate more intermediate reaches and were more responsive to changes in reward, suggesting these movements may reflect a strategy to maximize reward versus success. Together, these findings suggest that when faced with choice uncertainty, individuals adopt movement strategies consistent with their risk/reward attitude, preferentially biasing behavior toward exogenous rewards or endogenous success and consequently modulating the relative desirability of the available options.
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http://dx.doi.org/10.1523/ENEURO.0503-21.2022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007409PMC
April 2022

Thyroidal Transcriptomic Profiles of Pathoadaptive Responses to Congenital Hypothyroidism in XB130 Knockout Mice.

Cells 2022 03 12;11(6). Epub 2022 Mar 12.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.

Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130 mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130 and Xb130 mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130 mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130 mice may overlap with those from other mutations causing congenital hypothyroidism.
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http://dx.doi.org/10.3390/cells11060975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947158PMC
March 2022

Telehealth in outpatient delivery of palliative care: a prospective survey evaluation by patients and clinicians.

Intern Med J 2022 Jul 6;52(7):1144-1153. Epub 2022 Apr 6.

Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Melbourne, Victoria.

Background: In Australia during the COVID-19 pandemic new funding models were introduced to support telehealth consultations, resulting in their widescale adoption in palliative care service delivery. Clarity around the clinical circumstances and patient populations that might be most appropriate for telehealth models was required.

Aims: To evaluate patient and physician satisfaction, acceptability and utility of outpatient palliative care provision through telehealth.

Methods: This is a multi-site prospective, cross-sectional, observational study conducted during a time of significant public health restrictions. A survey was used to collect matched patient- and physician-reported perceptions of palliative care telehealth consultations across three metropolitan hospitals in Victoria, Australia.

Results: There were 127 matched patient-physician data of telehealth consultations and a further 812 physician-only assessments. Telehealth was generally acceptable and satisfactory, with patients providing greater positive scores than clinicians. Telehealth incorporating both audio and video were more acceptable and satisfactory, particularly with the presence of a carer, and during routine reviews. Physicians were less satisfied using telehealth when there was increasing symptom complexity across all domains (pain, psychological, and other symptoms).

Conclusions: Telehealth has high utility in palliative care practice. A future hybrid model of care comprising both face-to-face and telehealth consultations seems favoured by patients and physicians but must be accompanied by targeted support for specific patient groups to ensure equitable healthcare access. Further evaluation of telehealth during a time of fewer public health emergency measures and lower community anxiety is required to fully understand its ongoing role.
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http://dx.doi.org/10.1111/imj.15721DOI Listing
July 2022

Mechanisms of Human Motor Learning Do Not Function Independently.

Front Hum Neurosci 2021 4;15:785992. Epub 2022 Jan 4.

Moss Rehabilitation Research Institute, Elkins Park, PA, United States.

Human motor learning is governed by a suite of interacting mechanisms each one of which modifies behavior in distinct ways and rely on different neural circuits. In recent years, much attention has been given to one type of motor learning, called motor adaptation. Here, the field has generally focused on the interactions of three mechanisms: sensory prediction error SPE-driven, explicit (strategy-based), and reinforcement learning. Studies of these mechanisms have largely treated them as modular, aiming to model how the outputs of each are combined in the production of overt behavior. However, when examined closely the results of some studies also suggest the existence of additional interactions between the sub-components of each learning mechanism. In this perspective, we propose that these sub-component interactions represent a critical means through which different motor learning mechanisms are combined to produce movement; understanding such interactions is critical to advancing our knowledge of how humans learn new behaviors. We review current literature studying interactions between SPE-driven, explicit, and reinforcement mechanisms of motor learning. We then present evidence of sub-component interactions between SPE-driven and reinforcement learning as well as between SPE-driven and explicit learning from studies of people with cerebellar degeneration. Finally, we discuss the implications of interactions between learning mechanism sub-components for future research in human motor learning.
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http://dx.doi.org/10.3389/fnhum.2021.785992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764186PMC
January 2022

Comment on Ramos-Rincon et al. Palliative Sedation in COVID-19 End-of-Life Care. Retrospective Cohort Study. 2021, , 873.

Medicina (Kaunas) 2022 Jan 6;58(1). Epub 2022 Jan 6.

Marie Curie Palliative Care Research Department, Division of Psychiatry, University College London, London W1T 7NF, UK.

We read with interest the article by Ramos-Rincon and colleagues about patients with COVID-19 dying in acute medical wards in a Spanish University hospital [...].
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http://dx.doi.org/10.3390/medicina58010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778193PMC
January 2022

Proprioception-based movement goals support imitation and are disrupted in apraxia.

Cortex 2022 02 27;147:140-156. Epub 2021 Nov 27.

Moss Rehabilitation Research Institute, Elkins Park, PA, USA. Electronic address:

The ability to imitate observed actions serves as an efficient method for learning novel movements and is specifically impaired (without concomitant gross motor impairments) in the neurological disorder of limb apraxia, a disorder common after left hemisphere stroke. Research with apraxic patients has advanced our understanding of how people imitate. However, the role of proprioception in imitation has been rarely assessed directly. Prior work has proposed that proprioceptively sensed body position is transformed into a visual format, supporting the attainment of a desired imitation goal represented visually (i.e., how the movement should look when performed). In contrast, we hypothesized a more direct role for proprioception: we suggest that movement goals are also represented proprioceptively (i.e., how a desired movement should feel when performed), and the ability to represent or access such proprioceptive goals is deficient in apraxia. Using a novel imitation task in which a robot cued meaningless trajectories proprioceptively or visually, we probed the role of each sensory modality. We found that patients with left hemisphere stroke were disproportionately worse than controls at imitating when cued proprioceptively versus visually. This proprioceptive versus visual disparity was associated with apraxia severity as assessed by a traditional imitation task, but could not be explained by general proprioceptive impairment or speed-accuracy trade-offs. These data suggest that successful imitation depends in part on the ability to represent movement goals in terms of how those movements should feel, and that deficits in this ability contribute to imitation impairments in patients with apraxia.
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http://dx.doi.org/10.1016/j.cortex.2021.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8852218PMC
February 2022

Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion.

Blood Adv 2022 03;6(6):1780-1796

Department of Developmental Biology and.

How genetic haploinsufficiency contributes to the clonal dominance of hematopoietic stem cells (HSCs) in del(5q) myelodysplastic syndrome (MDS) remains unresolved. Using a genetic barcoding strategy, we performed a systematic comparison on genes implicated in the pathogenesis of del(5q) MDS in direct competition with each other and wild-type (WT) cells with single-clone resolution. Csnk1a1 haploinsufficient HSCs expanded (oligo)clonally and outcompeted all other tested genes and combinations. Csnk1a1-/+ multipotent progenitors showed a proproliferative gene signature and HSCs showed a downregulation of inflammatory signaling/immune response. In validation experiments, Csnk1a1-/+ HSCs outperformed their WT counterparts under a chronic inflammation stimulus, also known to be caused by neighboring genes on chromosome 5. We therefore propose a crucial role for Csnk1a1 haploinsufficiency in the selective advantage of 5q-HSCs, implemented by creation of a unique competitive advantage through increased HSC self-renewal and proliferation capacity, as well as increased fitness under inflammatory stress.
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http://dx.doi.org/10.1182/bloodadvances.2021006061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941465PMC
March 2022

Handling Missing Data and Drop Out in Hospice/Palliative Care Trials Through the Estimand Framework.

J Pain Symptom Manage 2022 04 23;63(4):e431-e439. Epub 2021 Dec 23.

Centre for Epidemiology and Biostatistics (S.B.), Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

Context: Missing data are common in hospice/palliative care randomized trials due to high drop-out because of the demographic of interest. It can introduce bias in the estimate of the treatment effect and its precision.

Objectives: The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) released updated guidance on statistical principles for clinical trials introducing the estimand framework to align trial objectives, trial conduct, statistical analysis and interpretation of results. Our objective is to present how the estimand framework can be used to guide the handling of missing data in palliative care trials.

Methods: We outline the estimand framework by highlighting the five elements of an estimand: treatment, population, variable, summary measure and intercurrent event handling. We list common intercurrent events in palliative care trials and present the five strategies for handling intercurrent events outlined in the ICH guidance.

Results: We describe common intercurrent events in palliative care trials and discuss and justify what analytic strategies could be followed with each. We provide an example using a palliative care trial comparing two opioids for pain relieve in participants with cancer pain.

Conclusion: When planning a palliative care trial, the estimand should be explicitly stated, including how intercurrent events will be handled in the analysis. This should be informed by the scientific objectives of the trial. The estimand guides the handling of missing data during the conduct and analysis of the trial. Defining an estimand is not a statistical activity, but a multi-disciplinary process involving all stakeholders.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.12.022DOI Listing
April 2022

Sex differences in assessing stenosis severity between physician visual assessment and quantitative coronary angiography.

Int J Cardiol 2022 Feb 3;348:9-14. Epub 2021 Dec 3.

National Heart Centre Singapore, Singapore; Duke-NUS Medical School, Singapore. Electronic address:

Background: Physician visual assessment (PVA) in invasive coronary angiography (ICA) is the current clinical method to determine stenosis severity and guide percutaneous coronary intervention. This study sought to evaluate the effect of sex differences in assessing coronary stenosis severity between PVA and quantitative coronary angiography (QCA).

Methods: 209 patients with coronary artery disease (288 coronary lesions) underwent ICA and fractional flow reserve (FFR). ICA image processing including PVA and QCA was used to quantify diameter stenosis (DS). The difference of DS (ΔDS) between PVA and QCA was defined as DS-DS. DS ≥50% was considered anatomically obstructive. FFR ≤0.8 was defined as myocardial ischemia.

Results: Mean ± SD age was 63 ± 9 years. There were no significant differences in DS (61.1 ± 16.3% vs 60.1 ± 18.9%) and DS (53.1 ± 12.1% vs 55.4 ± 14.3%) between females and males. However, ΔDS between PVA and QCA was higher in females (8.0 ± 10.9%) than in males (4.7 ± 10.9%) (P = 0.03). Thirty-four of 72 vessels (47.2%) in female patients and 75 of 216 vessels (34.7%) in male patients were classified differently by at least one grade using PVA compared to QCA assessment. DS and DS were negatively correlated with FFR in females (r = -0.397, r = -0.448) with an even stronger negative correlation in males (r = -0.607, r = -0.607). ROC analysis demonstrated that DS had better discrimination capability for myocardial ischemia (FFR ≤ 0.80) than DS in both sexes (P < 0.05).

Conclusions: A systematic bias was found in PVA (QCA reference) for overestimating severity of coronary artery disease in females compared to males.
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http://dx.doi.org/10.1016/j.ijcard.2021.11.089DOI Listing
February 2022

Palliative Care Clinical Trials: Building Capability and Capacity.

J Palliat Med 2022 03 17;25(3):421-427. Epub 2021 Nov 17.

Departments of Palliative Care and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Clinical trials are a key component of expanding the evidence base in palliative care. A key strategic objective of the Victorian Comprehensive Cancer Centre (VCCC), a multisite cancer center alliance, was to increase palliative care clinical trial expertise. The palliative care services within the VCCC alliance presented substantial trial development opportunities with large number of patients and established relationships, but few trial-active centers. To establish a multi-site "Building Capability in Palliative Care Clinical Trials" program as a service development, and to assess the strategies, activities, and the outcomes resulting from this program. A series of strategies and activities were developed linked to the key program objectives of increasing the number of clinical sites and skilled clinicians conducting clinical trials, increasing the number of trials available and patients participating, broadening research opportunities in palliative care, and establishing the program sustainability. In the two years of implementation, the program resulted in the establishment and conduct of several Phase 4 postmarketing pharmacovigilance studies, nine Phase 2 and 3 trials across five palliative care services, and a Phase 1 clinical trial. During the program, 150 patients were recruited to clinical trials, and 258 prospective pharmacovigilance monitoring cases were recorded. Five investigator-initiated trials were developed by clinical trial fellows and achieved competitive ( = 3) or commercial ( = 2) funding. Clinicians reported that undertaking clinical trials had increased attention to the evidence base of care provision, and increased service research activity more broadly. Long-term sustainability remains a challenge, particularly in the context of the COVID-19 pandemic. Clinical trials in palliative care services are feasible, acceptable, and result in increased attention to the evidence base of care. The strategies detailing the framework, activities, and outcomes have been collated to facilitate implementation of clinical trials in other sites and with other trial-naive disciplinary groups.
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http://dx.doi.org/10.1089/jpm.2021.0314DOI Listing
March 2022

Diagnostic Performance of Fractional Flow Reserve From CT Coronary Angiography With Analytical Method.

Front Cardiovasc Med 2021 20;8:739633. Epub 2021 Oct 20.

National Heart Centre Singapore, Singapore, Singapore.

The aim of this study was to evaluate a new analytical method for calculating non-invasive fractional flow reserve (FFR) to diagnose ischemic coronary lesions. Patients with suspected or known coronary artery disease (CAD) who underwent computed tomography coronary angiography (CTCA) and invasive coronary angiography (ICA) with FFR measurements from two sites were prospectively recruited. Obstructive CAD was defined as diameter stenosis (DS) ≥50% on CTCA or ICA. FFR was derived from CTCA images and anatomical features using analytical method and was compared with computational fluid dynamics (CFD)-based FFR (FFR) and invasive ICA-based FFR. FFR, FFR, and invasive FFR ≤ 0.80 defined ischemia. A total of 108 participants (mean age 60, range: 30-83 years, 75% men) with 169 stenosed coronary arteries were analyzed. The per-vessel accuracy, sensitivity, specificity, and positive predictive and negative predictive values were, respectively, 81, 75, 86, 81, and 82% for FFR and 87, 88, 86, 83, and 90% for FFR. The area under the receiver operating characteristics curve for FFR (0.89 and 0.87) and FFR (0.90 and 0.86) were higher than both CTCA- and ICA-derived DS (all < 0.0001) on per-vessel and per-patient bases for discriminating ischemic lesions. The computational time for FFR was much shorter than FFR (2.2 ± 0.9 min . 48 ± 36 min, excluding image acquisition and segmentation). FFR calculated from a novel and expeditious non-CFD approach possesses a comparable diagnostic performance to CFD-derived FFR, with a significantly shorter computational time.
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http://dx.doi.org/10.3389/fcvm.2021.739633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564016PMC
October 2021

CLiP, catheter and line position dataset.

Sci Data 2021 10 28;8(1):285. Epub 2021 Oct 28.

Department of Radiology, Alfred Health, Melbourne, Victoria, Australia.

Correct catheter position is crucial to ensuring appropriate function of the catheter and avoid complications. This paper describes a dataset consisting of 50,612 image level and 17,999 manually labelled annotations from 30,083 chest radiographs from the publicly available NIH ChestXRay14 dataset with manually annotated and segmented endotracheal tubes (ETT), nasoenteric tubes (NET) and central venous catheters (CVCs).
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http://dx.doi.org/10.1038/s41597-021-01066-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553862PMC
October 2021

COVID-19 pandemic, mechanical reperfusion and 30-day mortality in ST elevation myocardial infarction.

Heart 2022 03 28;108(6):458-466. Epub 2021 Oct 28.

Department of Cardiology, University of Patras, Patras, Greece.

Objective: The initial data of the International Study on Acute Coronary Syndromes - ST Elevation Myocardial Infarction COVID-19 showed in Europe a remarkable reduction in primary percutaneous coronary intervention procedures and higher in-hospital mortality during the initial phase of the pandemic as compared with the prepandemic period. The aim of the current study was to provide the final results of the registry, subsequently extended outside Europe with a larger inclusion period (up to June 2020) and longer follow-up (up to 30 days).

Methods: This is a retrospective multicentre registry in 109 high-volume primary percutaneous coronary intervention (PPCI) centres from Europe, Latin America, South-East Asia and North Africa, enrolling 16 674 patients with ST segment elevation myocardial infarction (STEMI) undergoing PPPCI in March/June 2019 and 2020. The main study outcomes were the incidence of PPCI, delayed treatment (ischaemia time >12 hours and door-to-balloon >30 min), in-hospital and 30-day mortality.

Results: In 2020, during the pandemic, there was a significant reduction in PPCI as compared with 2019 (incidence rate ratio 0.843, 95% CI 0.825 to 0.861, p<0.0001). This reduction was significantly associated with age, being higher in older adults (>75 years) (p=0.015), and was not related to the peak of cases or deaths due to COVID-19. The heterogeneity among centres was high (p<0.001). Furthermore, the pandemic was associated with a significant increase in door-to-balloon time (40 (25-70) min vs 40 (25-64) min, p=0.01) and total ischaemia time (225 (135-410) min vs 196 (120-355) min, p<0.001), which may have contributed to the higher in-hospital (6.5% vs 5.3%, p<0.001) and 30-day (8% vs 6.5%, p=0.001) mortality observed during the pandemic.

Conclusion: Percutaneous revascularisation for STEMI was significantly affected by the COVID-19 pandemic, with a 16% reduction in PPCI procedures, especially among older patients (about 20%), and longer delays to treatment, which may have contributed to the increased in-hospital and 30-day mortality during the pandemic.

Trial Registration Number: NCT04412655.
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http://dx.doi.org/10.1136/heartjnl-2021-319750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561823PMC
March 2022

Tracking strategy changes using machine learning classifiers.

Behav Res Methods 2022 Aug 26;54(4):1818-1840. Epub 2021 Oct 26.

Department of Psychology, Mississippi State University, PO Box 6161, Mississippi State, MS, 39762, USA.

In complex tasks, high performers often have better strategies than low performers, even with similar amounts of practice. Relatively little research has examined how people form and change strategies in tasks that permit a large set of strategies. One challenge with such research is identifying strategies based on behavior. Three algorithms were developed that track the task features people use in their strategies while performing a complex task. Two of these algorithms were based on task-general, machine-learning classifiers: a support vector machine and a decision tree algorithm. The third was a task-specific algorithm. Data from several strategies in a complex task were simulated, and the algorithms were tested to see how well they identified the underlying features of the simulated strategy. The two machine-learning classifiers performed better than the task-specific algorithm. However, the two classifiers differed on how well they identified different types of strategies. The first two studies show that the ability of these algorithms to recover the underlying strategy depends on the complexity of the strategy relative to the quantity of performance data available. If the underlying strategy changes too frequently, then the performance of the algorithms suffers. However, results from the third study show that it is possible to use these algorithms to track strategy changes that occur in a task. The fourth study examines performance on data from human participants. This approach to tracking strategy exploration may enable further development of theories about how people search for and select effective strategies.
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http://dx.doi.org/10.3758/s13428-021-01720-4DOI Listing
August 2022

Ischemia-Reperfusion Injury in a Simulated Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells.

Cells 2021 10 10;10(10). Epub 2021 Oct 10.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.

Current understanding of mechanisms of ischemia-reperfusion-induced lung injury during lung preservation and transplantation is mainly based on clinical observations and animal studies. Herein, we used cell and systems biology approaches to explore these mechanisms at transcriptomics levels, especially by focusing on the differences between human lung endothelial and epithelial cells, which are crucial for maintaining essential lung structure and function. Human pulmonary microvascular endothelial cells and human lung epithelial cells were cultured to confluent, subjected to different cold ischemic times (CIT) to mimic static cold storage with preservation solution, and then subjected to warm reperfusion with a serum containing culture medium to simulate lung transplantation. Cell morphology, viability, and transcriptomic profiles were studied. Ischemia-reperfusion injury induced a CIT time-dependent cell death, which was associated with dramatic changes in gene expression. Under normal control conditions, endothelial cells showed gene clusters enriched in the vascular process and inflammation, while epithelial cells showed gene clusters enriched in protein biosynthesis and metabolism. CIT 6 h alone or after reperfusion had little effect on these phenotypic characteristics. After CIT 18 h, protein-biosynthesis-related gene clusters disappeared in epithelial cells; after reperfusion, metabolism-related gene clusters in epithelial cells and multiple gene clusters in the endothelial cells also disappeared. Human pulmonary endothelial and epithelial cells have distinct phenotypic transcriptomic signatures. Severe cellular injury reduces these gene expression signatures in a cell-type-dependent manner. Therapeutics that preserve these transcriptomic signatures may represent new treatment to prevent acute lung injury during lung transplantation.
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http://dx.doi.org/10.3390/cells10102713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534993PMC
October 2021

Improved door-to-balloon time for primary percutaneous coronary intervention for patients conveyed via emergency ambulance service.

Ann Acad Med Singap 2021 09;50(9):671-678

Department of Emergency Medicine, Singapore General Hospital, Singapore.

Introduction: Early reperfusion of ST-segment elevation myocardial infarction (STEMI) results in better outcomes. Interventions that have resulted in shorter door-to-balloon (DTB) time include prehospital cardiovascular laboratory activation and prehospital electrocardiogram (ECG) transmission, which are only available for patients who arrive via emergency ambulances. We assessed the impact of mode of transport on DTB time in a single tertiary institution and evaluated the factors that affected various components of DTB time.

Methods: We conducted a retrospective cohort study using registry data of patients diagnosed with STEMI in the emergency department (ED) who underwent primary percutaneous coronary intervention. We compared patients who arrived by emergency ambulances with those who came via their own transport. The primary study end point was DTB, defined as the earliest time a patient arrived in the ED to balloon inflation. As deidentified data was used, ethics review was waived.

Results: A total of 321 patients were included for analysis after excluding 7 with missing data. The mean age was 61.4±11.4 years old with 49 (15.3%) females. Ninety-nine (30.8%) patients arrived by emergency ambulance. The median DTB time was shorter for patients arriving by ambulance versus own transport (52min, interquartile range [IQR] 45-61 vs 67min, IQR 59-74; <0.001), with shorter door-to-ECG and door-to-activation time.

Conclusion: Arrival via emergency ambulance was associated with a decreased DTB for STEMI patients compared to arriving via own transport. There is a need for public education to increase the usage of emergency ambulances for suspected heart attacks to improve outcomes.
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September 2021

Spatial transcriptional mapping of the human nephrogenic program.

Dev Cell 2021 08;56(16):2381-2398.e6

Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Congenital abnormalities of the kidney and urinary tract are among the most common birth defects, affecting 3% of newborns. The human kidney forms around a million nephrons from a pool of nephron progenitors over a 30-week period of development. To establish a framework for human nephrogenesis, we spatially resolved a stereotypical process by which equipotent nephron progenitors generate a nephron anlage, then applied data-driven approaches to construct three-dimensional protein maps on anatomical models of the nephrogenic program. Single-cell RNA sequencing identified progenitor states, which were spatially mapped to the nephron anatomy, enabling the generation of functional gene networks predicting interactions within and between nephron cell types. Network mining identified known developmental disease genes and predicted targets of interest. The spatially resolved nephrogenic program made available through the Human Nephrogenesis Atlas (https://sckidney.flatironinstitute.org/) will facilitate an understanding of kidney development and disease and enhance efforts to generate new kidney structures.
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http://dx.doi.org/10.1016/j.devcel.2021.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396064PMC
August 2021

Use of sodium zirconium cyclosilicate for up-titration of renin-angiotensin-aldosterone system inhibitor therapy in patients with heart failure: a case series.

Eur Heart J Case Rep 2021 Aug 15;5(8):ytab281. Epub 2021 Aug 15.

Cardiology Department, Princess of Wales Hospital, Coity Road, Bridgend, Wales CF31 1RQ, UK.

Background: Patients often receive suboptimal dosing of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy over concerns of hyperkalaemia. However, studies have shown associations between suboptimal dosing or interruptions to therapy and adverse clinical events. Therefore, effective treatments for hyperkalaemia that can enable optimal RAASi therapy are needed. This case series examines eight patients whose commencement on the novel potassium binder sodium zirconium cyclosilicate (SZC) allowed for the initiation and/or up-titration of RAASi therapy.

Case Summary: Eight patients aged 64-87 years with heart failure (HF) with reduced ejection fraction all developed hyperkalaemia (serum potassium (sK) >5.0 mmol/L) while receiving RAASi therapy. Following initiation of SZC, all patients experienced eventual stabilization of sK levels. All patients were able to initiate, restart, or up-titrate RAASi therapy with five patients achieving optimal medical therapy. Left ventricular ejection fraction improved in four patients, two patients are now re-classified as New York Heart Association Class I, and an additional patient had improved exercise tolerance. Follow-up for Patient 8 is still ongoing.

Discussion: These real-world cases demonstrate that use of SZC to manage hyperkalaemia in patients with HF is feasible and allows optimization of RAASi therapy.
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http://dx.doi.org/10.1093/ehjcr/ytab281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364764PMC
August 2021

Decoding disease: from genomes to networks to phenotypes.

Nat Rev Genet 2021 12 2;22(12):774-790. Epub 2021 Aug 2.

Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA.

Interpreting the effects of genetic variants is key to understanding individual susceptibility to disease and designing personalized therapeutic approaches. Modern experimental technologies are enabling the generation of massive compendia of human genome sequence data and associated molecular and phenotypic traits, together with genome-scale expression, epigenomics and other functional genomic data. Integrative computational models can leverage these data to understand variant impact, elucidate the effect of dysregulated genes on biological pathways in specific disease and tissue contexts, and interpret disease risk beyond what is feasible with experiments alone. In this Review, we discuss recent developments in machine learning algorithms for genome interpretation and for integrative molecular-level modelling of cells, tissues and organs relevant to disease. More specifically, we highlight existing methods and key challenges and opportunities in identifying specific disease-causing genetic variants and linking them to molecular pathways and, ultimately, to disease phenotypes.
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http://dx.doi.org/10.1038/s41576-021-00389-xDOI Listing
December 2021

Dissociable theta networks underlie the switch and mixing costs during task switching.

Hum Brain Mapp 2021 10 29;42(14):4643-4657. Epub 2021 Jun 29.

Functional Neuroimaging Laboratory, School of Psychology, University of Newcastle, Callaghan, New South Wales, Australia.

During task-switching paradigms, both event-related potentials and time-frequency analyses show switch and mixing effects at frontal and parietal sites. Switch and mixing effects are associated with increased power in broad frontoparietal networks, typically stronger in the theta band (~4-8 Hz). However, it is not yet known whether mixing and switch costs rely upon common or distinct networks. In this study, we examine proactive and reactive control networks linked to task switching and mixing effects, and whether strength of connectivity in these networks is associated with behavioural outcomes. Participants (n = 197) completed a cued-trials task-switching paradigm with concurrent electroencephalography, after substantial task practice to establish strong cue-stimulus-response representations. We used inter-site phase clustering, a measure of functional connectivity across electrode sites, to establish cross-site connectivity from a frontal and a parietal seed. Distinct theta networks were activated during proactive and reactive control periods. During the preparation interval, mixing effects were associated with connectivity from the frontal seed to parietal sites, and switch effects with connectivity from the parietal seed to occipital sites. Lateralised occipital connectivity was common to both switch and mixing effects. After target onset, frontal and parietal seeds showed a similar pattern of connectivity across trial types. These findings are consistent with distinct and common proactive control networks and common reactive networks in highly practised task-switching performers.
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http://dx.doi.org/10.1002/hbm.25573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410519PMC
October 2021
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