Publications by authors named "Christopher Clark"

423 Publications

On the potential for mapping apparent neural soma density via a clinically viable diffusion MRI protocol.

Neuroimage 2021 Jun 23;239:118303. Epub 2021 Jun 23.

Centre for Medical Image Computing, Department of Computer Science, University College London, London, United Kingdom; Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Diffusion MRI is a valuable tool for probing tissue microstructure in the brain noninvasively. Today, model-based techniques are widely available and used for white matter characterisation where their development is relatively mature. Conversely, tissue modelling in grey matter is more challenging, and no generally accepted models exist. With advances in measurement technology and modelling efforts, a clinically viable technique that reveals salient features of grey matter microstructure, such as the density of quasi-spherical cell bodies and quasi-cylindrical cell projections, is an exciting prospect. As a step towards capturing the microscopic architecture of grey matter in clinically feasible settings, this work uses a biophysical model that is designed to disentangle the diffusion signatures of spherical and cylindrical structures in the presence of orientation heterogeneity, and takes advantage of B-tensor encoding measurements, which provide additional sensitivity compared to standard single diffusion encoding sequences. For the fast and robust estimation of microstructural parameters, we leverage recent advances in machine learning and replace conventional fitting techniques with an artificial neural network that fits complex biophysical models within seconds. Our results demonstrate apparent markers of spherical and cylindrical geometries in healthy human subjects, and in particular an increased volume fraction of spherical compartments in grey matter compared to white matter. We evaluate the extent to which spherical and cylindrical geometries may be interpreted as correlates of neural soma and neural projections, respectively, and quantify parameter estimation errors in the presence of various departures from the modelling assumptions. While further work is necessary to translate the ideas presented in this work to the clinic, we suggest that biomarkers focussing on quasi-spherical cellular geometries may be valuable for the enhanced assessment of neurodevelopmental disorders and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118303DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Systolic blood pressure and outcomes in frail older adults.

Br J Hosp Med (Lond) 2021 May 26;82(5):1-4. Epub 2021 May 26.

College of Medicine and Health, University of Exeter Medical School, UK.

Hypertension is diagnosed in the majority of older people with frailty, in whom blood pressure prognosis is not well understood. This editorial describes recent evidence on blood pressure and outcomes in older people with frailty.
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http://dx.doi.org/10.12968/hmed.2021.0181DOI Listing
May 2021

Blasting the myth of predictive INR changes related to plasma transfusion: an academic institution's experience.

Hematol Transfus Cell Ther 2021 May 4. Epub 2021 May 4.

The University of Tennessee Medical Center, Knoxville, TN, United States.

Introduction: Plasma transfusion is a common therapeutic strategy used to lower international normalized ratio (INR) values in the non-emergent setting. However, due to lack of evidence of its efficacy, standardized guidelines for this practice have not been well established.

Methods: This retrospective observational cohort study analyzed 276 inpatient encounters that involved plasma transfusions focusing on change in INR values from pre- to post-transfusion, with respect to the following predictor variables: vitamin K co-administration, number of plasma units transfused, order indication and body mass index (BMI).

Results: The overall average change in the INR was 1.35. Patients who received vitamin K showed an average change of 2.51, while patients that did not receive vitamin K demonstrated an average change of 0.70. Increased numbers of plasma units transfused showed benefit up to three-unit orders. Greater decreases in the INR were observed for patients requiring plasma for anticoagulation reversal or active bleeding. There was no significant difference in the change in INR based on the BMI. By multivariate and regression analyses, the stepwise addition of each successive predictor variable demonstrated an increase in the shared variance in the outcome of the post-transfusion INR: the pre-transfusion INR and vitamin K co-administration alone was not significant (p = 0.45); the additional number of plasma units transfused was significant (R² = 0.13, p < 0.001), and; the subsequent additional plasma order indications (R² = 0.19, p < 0.001) and BMI (R² = 0.18, p < 0.001) were increasingly significant.

Conclusion: Taking into consideration the combination of multiple predictive factors may aid in a more efficient use of plasma products.
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http://dx.doi.org/10.1016/j.htct.2021.01.015DOI Listing
May 2021

Tail control enhances gliding in arboreallizards: an integrative study using a 3D geometric model and numerical simulation.

Integr Comp Biol 2021 May 19. Epub 2021 May 19.

Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA92521, USA.

The ability to glide through an arboreal habitat has been acquired by several mammals, amphibians, snakes, lizards, and even invertebrates. Lizards of the genus Draco possess specialized morphological structures for gliding, including a patagium, throat lappets, and modified hindlimbs. Despite being among the most specialized reptilian gliders, it is currently unknown how Draco are able to maneuver effectively during flight. Here, we present a new computational method for characterizing the role of tail control on Draco glide distance and stability. We first modeled Draco flight dynamics as a function of gravitational, lift, and drag forces. Lift and drag estimates were derived from wind tunnel experiments of 3 D printed models based on photos of Draco during gliding. Initial modeling leveraged the known mass and planar surface area of the Draco to estimate lift and drag coefficients. We developed a simplified, three-dimensional simulation for Draco gliding, calculating longitudinal and lateral position and pitch angle of the lizard with respect to a cartesian coordinate frame. We used PID control to model the lizards' tail adjustment to maintain an angle of attack. Our model suggests an active tail improves both glide distance and stability in Draco. These results provide insight towards the biomechanics of Draco; however future in-vivo studies are needed to provide a complete picture for gliding mechanics of this genus. Our approach enables the replication and modification of existing gliders in order to better understand their performance and mechanics. This can be applied to extinct species, but also as a way of exploring the biomimetic potential of different morphological features.
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http://dx.doi.org/10.1093/icb/icab073DOI Listing
May 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

Solitary scalp nodule-A diagnostic dilemma.

Diagn Cytopathol 2021 Jun 21;49(6):779-781. Epub 2021 Apr 21.

Department of Pathology, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA.

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http://dx.doi.org/10.1002/dc.24747DOI Listing
June 2021

Corollary discharge promotes a sustained motor state in a neural circuit for navigation.

Elife 2021 Apr 21;10. Epub 2021 Apr 21.

Department of Physics and Center for Brain Science, Harvard University, Cambridge, United States.

Animals exhibit behavioral and neural responses that persist on longer timescales than transient or fluctuating stimulus inputs. Here, we report that uses feedback from the motor circuit to a sensory processing interneuron to sustain its motor state during thermotactic navigation. By imaging circuit activity in behaving animals, we show that a principal postsynaptic partner of the AFD thermosensory neuron, the AIY interneuron, encodes both temperature and motor state information. By optogenetic and genetic manipulation of this circuit, we demonstrate that the motor state representation in AIY is a corollary discharge signal. RIM, an interneuron that is connected with premotor interneurons, is required for this corollary discharge. Ablation of RIM eliminates the motor representation in AIY, allows thermosensory representations to reach downstream premotor interneurons, and reduces the animal's ability to sustain forward movements during thermotaxis. We propose that feedback from the motor circuit to the sensory processing circuit underlies a positive feedback mechanism to generate persistent neural activity and sustained behavioral patterns in a sensorimotor transformation.
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http://dx.doi.org/10.7554/eLife.68848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139836PMC
April 2021

An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer's disease.

Alzheimers Res Ther 2021 04 1;13(1):71. Epub 2021 Apr 1.

Old Age Psychiatry, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, 1011, Lausanne, Switzerland.

Background: Multiple pathophysiological processes have been described in Alzheimer's disease (AD). Their inter-individual variations, complex interrelations, and relevance for clinical manifestation and disease progression remain poorly understood. We hypothesize that specific molecular patterns indicating both known and yet unidentified pathway alterations are associated with distinct aspects of AD pathology.

Methods: We performed multi-level cerebrospinal fluid (CSF) omics in a well-characterized cohort of older adults with normal cognition, mild cognitive impairment, and mild dementia. Proteomics, metabolomics, lipidomics, one-carbon metabolism, and neuroinflammation related molecules were analyzed at single-omic level with correlation and regression approaches. Multi-omics factor analysis was used to integrate all biological levels. Identified analytes were used to construct best predictive models of the presence of AD pathology and of cognitive decline with multifactorial regression analysis. Pathway enrichment analysis identified pathway alterations in AD.

Results: Multi-omics integration identified five major dimensions of heterogeneity explaining the variance within the cohort and differentially associated with AD. Further analysis exposed multiple interactions between single 'omics modalities and distinct multi-omics molecular signatures differentially related to amyloid pathology, neuronal injury, and tau hyperphosphorylation. Enrichment pathway analysis revealed overrepresentation of the hemostasis, immune response, and extracellular matrix signaling pathways in association with AD. Finally, combinations of four molecules improved prediction of both AD (protein 14-3-3 zeta/delta, clusterin, interleukin-15, and transgelin-2) and cognitive decline (protein 14-3-3 zeta/delta, clusterin, cholesteryl ester 27:1 16:0 and monocyte chemoattractant protein-1).

Conclusions: Applying an integrative multi-omics approach we report novel molecular and pathways alterations associated with AD pathology. These findings are relevant for the development of personalized diagnosis and treatment approaches in AD.
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http://dx.doi.org/10.1186/s13195-021-00814-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015070PMC
April 2021

Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer's disease pathology and clinical disease progression.

Alzheimers Res Ther 2021 03 25;13(1):65. Epub 2021 Mar 25.

Old age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting.

Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression.

Results: Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ, and Aβ/Aβ in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants.

Conclusion: Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.
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http://dx.doi.org/10.1186/s13195-021-00805-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995778PMC
March 2021

The contribution of wildland fire emissions to deposition in the U S: implications for tree growth and survival in the Northwest.

Environ Res Lett 2021 Jan;16(2)

Center for Environmental Measurement and Modeling, US EPA, Cincinnati, OH, United States of America.

Ecosystems require access to key nutrients like nitrogen (N) and sulfur (S) to sustain growth and healthy function. However, excessive deposition can also damage ecosystems through nutrient imbalances, leading to changes in productivity and shifts in ecosystem structure. While wildland fires are a known source of atmospheric N and S, little has been done to examine the implications of wildland fire deposition for vulnerable ecosystems. We combine wildland fire emission estimates, atmospheric chemistry modeling, and forest inventory data to (a) quantify the contribution of wildland fire emissions to N and S deposition across the U S, and (b) assess the subsequent impacts on tree growth and survival rates in areas where impacts are likely meaningful based on the relative contribution of fire to total deposition. We estimate that wildland fires contributed 0.2 kg N ha yr and 0.04 kg S ha yr on average across the U S during 2008-2012, with maxima up to 1.4 kg N ha yr and 0.6 kg S ha yr in the Northwest representing over ~30% of total deposition in some areas. Based on these fluxes, exceedances of S critical loads as a result of wildland fires are minimal, but exceedances for N may affect the survival and growth rates of 16 tree species across 4.2 million hectares, with the most concentrated impacts occurring in Oregon, northern California, and Idaho. Understanding the broader environmental impacts of wildland fires in the U S will inform future decision making related to both fire management and ecosystem services conservation.
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http://dx.doi.org/10.1088/1748-9326/abd26eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970516PMC
January 2021

Arm Based on LEg blood pressures (ABLE-BP): can systolic leg blood pressure measurements predict systolic brachial blood pressure? Protocol for an individual participant data meta-analysis from the INTERPRESS-IPD Collaboration.

BMJ Open 2021 03 19;11(3):e040481. Epub 2021 Mar 19.

Primary Care Research Group, University of Exeter, Exeter, UK

Introduction: Blood pressure (BP) is normally measured on the upper arm, and guidelines for the diagnosis and treatment of high BP are based on such measurements. Leg BP measurement can be an alternative when brachial BP measurement is impractical, due to injury or disability. Limited data exist to guide interpretation of leg BP values for hypertension management; study-level systematic review findings suggest that systolic BP (SBP) is 17 mm Hg higher in the leg than the arm. However, uncertainty remains about the applicability of this figure in clinical practice due to substantial heterogeneity.

Aims: To examine the relationship between arm and leg SBP, develop and validate a multivariable model predicting arm SBP from leg SBP and investigate the prognostic association between leg SBP and cardiovascular disease and mortality.

Methods And Analysis: Individual participant data (IPD) meta-analyses using arm and leg SBP measurements for 33 710 individuals from 14 studies within the Inter-arm blood pressure difference IPD (INTERPRESS-IPD) Collaboration. We will explore cross-sectional relationships between arm and leg SBP using hierarchical linear regression with participants nested by study, in multivariable models. Prognostic models will be derived for all-cause and cardiovascular mortality and cardiovascular events.

Ethics And Dissemination: Data originate from studies with prior ethical approval and consent, and data sharing agreements are in place-no further approvals are required to undertake the secondary analyses proposed in this protocol. Findings will be published in peer-reviewed journal articles and presented at conferences. A comprehensive dissemination strategy is in place, integrated with patient and public involvement.

Prospero Registration Number: CRD42015031227.
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http://dx.doi.org/10.1136/bmjopen-2020-040481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986760PMC
March 2021

Ways that animal wings produce sound.

Integr Comp Biol 2021 Mar 8. Epub 2021 Mar 8.

Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA 92521, USA.

There are at least eight ways that wings potentially produce sound. Five mechanisms are aerodynamic sounds, created by airflow, and three are structural sound created by interactions of solid surfaces. Animal flight is low Mach (M), meaning all animals move at less than 30% of the speed of sound. Thus in aerodynamic mechanisms the effects of air compressibility can be ignored, except in mechanism #1. Mechanism #1 is trapped air, in which air approaches or exceeds Mach 1 as it escapes a constriction. This mechanism is hypothetical but likely. #2 is Gutin sound, the aerodynamic reaction to lift and drag. This mechanism is ubiquitous in flight, and generates low frequency sound such as the humming of hummingbirds or insect wing tones. #3 is turbulence-generated atonal whooshing sounds, which are also widespread in animal flight. #4 are whistles, tonal sounds generated by geometry-induced flow feedback. This mechanism is hypothetical. #5 is aeroelastic flutter, sound generated by elasticity-induced feedback that is usually but not always tonal. This is widespread in birds (feathers are predisposed to flutter) but apparently not bats or insects. Mechanism #6 is rubbing sound (including stridulation), created when bird feathers or insect wings slide past each other. Atonal rubbing sounds are widespread in bird flight and insects; tonal stridulation is widespread in insects. #7 is percussion, created when two stiff elements collide and vibrate, and is present in some birds and insects. Mechanism #8 are tymbals and other bistable conformations. These are stiff elements that snap back and forth between two conformations, producing impulsive, atonal sound. Tymbals are widespread in insects but not birds or bats; insect cuticle appears predisposed to form tymbals. There are few examples of bat wing sounds: are bats intrinsically quiet, or just under-studied? These mechanisms, especially Gutin sound, whooshes, and rubbing (#2, #3, and #6) are prominent cues in ordinary flight of all flying animals, and are the 'acoustic substrate' available to be converted from an adventitious sound (cue) into a communication signal. For instance, wing sounds have many times evolved into signals that are incorporated into courtship displays. Conversely, these are the sounds selected to be suppressed if quiet flight is selected for. The physical mechanisms that underlie animal sounds provides context for understanding the ways in which signals and cues may evolve.
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http://dx.doi.org/10.1093/icb/icab008DOI Listing
March 2021

Sphenopalatine ganglion block for the treatment of acute headache: An old treatment revisited.

Am J Emerg Med 2021 Feb 6. Epub 2021 Feb 6.

Spectrum Health - Michigan State University Emergency Medicine Residency Program, 15 Michigan St NE, Suite 701, Grand Rapids, MI 49503, United States. Electronic address:

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http://dx.doi.org/10.1016/j.ajem.2021.02.007DOI Listing
February 2021

International public awareness of peripheral artery disease.

Vasa 2021 07 1;50(4):294-300. Epub 2021 Mar 1.

Department of Cardiology, Dupuytren University Hospital, Limoges, France.

: Peripheral artery disease (PAD) of the lower limbs is a common condition with considerable global burden. Some country-specific studies suggest low levels of public awareness. To our knowledge public awareness of PAD has never been assessed simultaneously in several countries worldwide. : This was an international, general public, internet-based quantitative survey assessing vascular health and disease understanding. Questionnaires included 23 closed-ended multiple-choice, Likert scale and binary choice questions. Data were collected from 9,098 survey respondents from nine countries in Europe, North and Latin America during May-June 2018. : Overall, familiarity with PAD was low (57% of respondents were "not at all familiar", and 9% were "moderately" or "very familiar"). Knowledge about PAD health consequences was limited, with 55% of all respondents not being aware of limb consequences of PAD. There were disparities in PAD familiarity levels between countries; highest levels of self-reported awareness were in Germany and Poland where 13% reported to be "very" or "moderately" familiar with PAD, and lowest in Scandinavian countries (5%, 3% and 2% of respondents in Norway, Sweden and Denmark, respectively). There were disparities in awareness according to age. Respondents aged 25-34 were most familiar with PAD, with 12% stating that they were "moderately" or "very" familiar with the condition, whereas those aged 18-24 were the least familiar with PAD (7% "moderately" or "very" familiar with PAD). In the 45-54, 55-64 and 65+ age groups, 9% said they were "moderately" or "very" familiar with the term. There was no important gender-based difference in PAD familiarity. : On an international level, public self-reported PAD awareness is low, even though PAD is a common condition with considerable burden. Campaigns to increase PAD awareness are needed to reduce delays in diagnosis and to motivate people to control PAD risk factors.
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http://dx.doi.org/10.1024/0301-1526/a000945DOI Listing
July 2021

Limited vocal compensation for elevated ambient noise in bearded seals: implications for an industrializing Arctic Ocean.

Proc Biol Sci 2021 02 24;288(1945):20202712. Epub 2021 Feb 24.

Center for Conservation Bioacoustics, Cornell Laboratory of Ornithology, Cornell University, Ithaca, NY 14850, USA.

Vocalizing animals have several strategies to compensate for elevated ambient noise. These behaviours evolved under historical conditions, but compensation limits are quickly being reached in the Anthropocene. Acoustic communication is essential to male bearded seals that vocalize for courtship and defending territories. As Arctic sea ice declines, industrial activities and associated anthropogenic noise are likely to increase. Documenting how seals respond to noise and identifying naturally occurring behavioural thresholds would indicate either their resilience or vulnerability to changing soundscapes. We investigated whether male bearded seals modified call amplitudes in response to changing ambient noise levels. Vocalizing seals increased their call amplitudes until ambient noise levels reached an observable threshold, above which call source levels stopped increasing. The presence of a threshold indicates limited noise compensation for seals, which still renders them vulnerable to acoustic masking of vocal signals. This behavioural threshold and response to noise is critical for developing management plans for an industrializing Arctic.
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http://dx.doi.org/10.1098/rspb.2020.2712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934916PMC
February 2021

The population genetics of nonmigratory Allen's Hummingbird () following a recent mainland colonization.

Ecol Evol 2021 Feb 20;11(4):1850-1865. Epub 2021 Jan 20.

Department of Evolution, Ecology, and Organismal Biology Speith Hall University of California Riverside CA USA.

Allen's Hummingbird comprises two subspecies, one migratory () and one nonmigratory (). The nonmigratory subspecies, previously endemic to the California Channel Islands, apparently colonized the California mainland on the Palos Verdes Peninsula some time before 1970 and now breeds throughout coastal southern California. We sequenced and compared populations of mainland nonmigratory Allen's Hummingbird to Channel Island populations from Santa Catalina, San Clemente, and Santa Cruz Island. We found no evidence of founder effects on the mainland population. Values of nucleotide diversity on the mainland were higher than on the Channel Islands. There were low levels of divergence between the Channel Islands and the mainland, and Santa Cruz Island was the most genetically distinct. Ecological niche models showed that rainfall and temperature variables on the Channel Islands are similar in the Los Angeles basin and predicted continued expansion of nonmigratory Allen's Hummingbird north along the coast and inland. We also reviewed previous genetic studies of vertebrate species found on the Channel Islands and mainland and showed that broad conclusions regarding island-mainland patterns remain elusive. Challenges include the idiosyncratic nature of colonization itself as well as the lack of a comprehensive approach that incorporates similar markers and sampling strategies across taxa, which, within the context of a comparative study of island-mainland relationships, may lead to inconsistent results.
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http://dx.doi.org/10.1002/ece3.7174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882939PMC
February 2021

International approaches to protecting and retaining trees on private urban land.

J Environ Manage 2021 May 6;285:112081. Epub 2021 Feb 6.

School of Ecosystem and Forest Science (SEFS), Burnley campus, Faculty of Science, The University of Melbourne, 500 Yarra Boulevard, Richmond, Victoria, 3121, Australia. Electronic address:

Most studies of urban forest management look at vegetation on public land. Yet, to meet ambitious urban forest targets, cities must attempt to maintain or increase trees and canopy cover on private urban land too. In this study, we review and evaluate international approaches to protecting and retaining trees on private urban land. Our study combines a systematic academic literature review, two empirical social science studies on the views of urban forest professionals, and a global case study review of innovative regulations and incentives aimed at protecting and retaining trees on private urban land. Case studies were evaluated for the extent they exceeded minimum standards or went beyond 'business-as-usual'. We found that the most innovative mechanisms combine many regulations, instead of relying on a single regulation, and use financial incentives to retain or plant trees in newly developed or re-developed sites, as well as private residences. We did not find any cases where appropriate monitoring was in place to determine the efficacy and efficiency of these mechanisms. We also found no single simple solution that could effectively and efficiently protect and retain trees on private land. Only by combining policies, planning schemes, local laws, and financial incentives with community engagement and stewardship will cities protect and retain trees on private land. Useful and innovative ways to protecting and retaining trees on private land involves providing solutions at multiple governments levels, embedding trees in existing strategic policy and management solutions, incentivising positive behavior, creating regulations that require payment up front, and engaging the broader community in private tree stewardship.
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http://dx.doi.org/10.1016/j.jenvman.2021.112081DOI Listing
May 2021

Factors associated with subjective cognitive decline in dementia-free older adults-A population-based study.

Int J Geriatr Psychiatry 2021 Aug 16;36(8):1188-1196. Epub 2021 Mar 16.

Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.

Background: Subjective cognitive decline (SCD) is common in older adults, affects quality of life (QoL), and may represent the earliest clinical manifestation of cognitive decline evolving to dementia. Still little is known about factors associated with SCD.

Objectives: (1) Assess the associations between SCD and demographic, social, clinical, and personality characteristics as well as QoL, with and without adjustment for objective cognitive performance, and (2) investigate the relations between neuroticism, QoL, and SCD.

Methods: Cross-sectional analysis of a cohort of 1567 dementia-free community-dwellers from the urban area of Lausanne, Switzerland, aged 64 years and older (mean age 70.9 ± 4.7 years), from CoLaus/PsyCoLaus. SCD was assessed using a validated 10-item questionnaire. Personality traits, QoL, and perceived social support were evaluated using self-report measures. Information on depression and anxiety status and socioeconomic characteristics including professional activity were elicited using a semi-structured interview. Cognitive functioning was assessed through a comprehensive neuropsychological test battery. Statistical analysis was based on logistic regression.

Results: SCD was present in 18.5% of the sample and it was associated with lower performance in memory and verbal fluency tasks. After controlling for possible confounders, professional activity, neuroticism, and current depression were associated with SCD. Exploratory analysis revealed associations of SCD with QoL, neuroticism, and their interaction.

Conclusion: Besides objective cognitive performance, SCD is related to several psychosocial factors in dementia-free community-dwelling older people. These findings are relevant for the development of healthcare interventions to reduce cognitive complaints, improve QoL, and prevent cognitive decline in general population.
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http://dx.doi.org/10.1002/gps.5509DOI Listing
August 2021

Author Correction: A cytochrome c is the natural electron acceptor for nicotine oxidoreductase.

Nat Chem Biol 2021 Mar;17(3):360

Department of Chemistry, Western Michigan University, Kalamazoo, MI, USA.

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http://dx.doi.org/10.1038/s41589-021-00756-zDOI Listing
March 2021

Classification of paediatric brain tumours by diffusion weighted imaging and machine learning.

Sci Rep 2021 Feb 4;11(1):2987. Epub 2021 Feb 4.

Institute of Cancer and Genomic Sciences, School of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10 mm s with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.
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http://dx.doi.org/10.1038/s41598-021-82214-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862387PMC
February 2021

COVID-19 and hypertension: risks and management. A scientific statement on behalf of the British and Irish Hypertension Society.

J Hum Hypertens 2021 04 22;35(4):304-307. Epub 2021 Jan 22.

Birmingham Medical School, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

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http://dx.doi.org/10.1038/s41371-020-00451-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821986PMC
April 2021

Man vs. Machine: Comparing Physician vs. Electronic Health Record-Based Model Predictions for 30-Day Hospital Readmissions.

J Gen Intern Med 2021 Jan 14. Epub 2021 Jan 14.

Department of Internal Medicine, UT Southwestern, Dallas, TX, USA.

Background: Electronic health record (EHR)-based readmission risk prediction models can be automated in real-time but have modest discrimination and may be missing important readmission risk factors. Clinician predictions of readmissions may incorporate information unavailable in the EHR, but the comparative usefulness is unknown. We sought to compare clinicians versus a validated EHR-based prediction model in predicting 30-day hospital readmissions.

Methods: We conducted a prospective survey of internal medicine clinicians in an urban safety-net hospital. Clinicians prospectively predicted patients' 30-day readmission risk on 5-point Likert scales, subsequently dichotomized into low- vs. high-risk. We compared human with machine predictions using discrimination, net reclassification, and diagnostic test characteristics. Observed readmissions were ascertained from a regional hospitalization database. We also developed and assessed a "human-plus-machine" logistic regression model incorporating both human and machine predictions.

Results: We included 1183 hospitalizations from 106 clinicians, with a readmission rate of 20.8%. Both clinicians and the EHR model had similar discrimination (C-statistic 0.66 vs. 0.66, p = 0.91). Clinicians had higher specificity (79.0% vs. 48.9%, p < 0.001) but lower sensitivity (43.9 vs. 75.2%, p < 0.001) than EHR model predictions. Compared with machine, human was better at reclassifying non-readmissions (non-event NRI + 30.1%) but worse at reclassifying readmissions (event NRI - 31.3%). A human-plus-machine approach best optimized discrimination (C-statistic 0.70, 95% CI 0.67-0.74), sensitivity (65.5%), and specificity (66.7%).

Conclusion: Clinicians had similar discrimination but higher specificity and lower sensitivity than EHR model predictions. Human-plus-machine was better than either alone. Readmission risk prediction strategies should incorporate clinician assessments to optimize the accuracy of readmission predictions.
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http://dx.doi.org/10.1007/s11606-020-06355-3DOI Listing
January 2021

A cytochrome c is the natural electron acceptor for nicotine oxidoreductase.

Nat Chem Biol 2021 03 11;17(3):344-350. Epub 2021 Jan 11.

Department of Chemistry, Western Michigan University, Kalamazoo, MI, USA.

Nicotine oxidoreductase (NicA2), a member of the flavin-containing amine oxidase family, is of medical relevance as it shows potential as a therapeutic to aid cessation of smoking due to its ability to oxidize nicotine into a non-psychoactive metabolite. However, the use of NicA2 in this capacity is stymied by its dismal O-dependent activity. Unlike other enzymes in the amine oxidase family, NicA2 reacts very slowly with O, severely limiting its nicotine-degrading activity. Instead of using O as an oxidant, we discovered that NicA2 donates electrons to a cytochrome c, which means that NicA2 is actually a dehydrogenase. This is surprising, as enzymes of the flavin-containing amine oxidase family were invariably thought to use O as an electron acceptor. Our findings establish new perspectives for engineering this potentially useful therapeutic and prompt a reconsideration of the term 'oxidase' in referring to members of the flavin-containing amine 'oxidase' family.
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http://dx.doi.org/10.1038/s41589-020-00712-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904663PMC
March 2021

Prevalence of postural hypotension in primary, community and institutional care: a systematic review and meta-analysis.

BMC Fam Pract 2021 01 2;22(1). Epub 2021 Jan 2.

Primary Care Research Group, University of Exeter Medical School, College of Medicine and Health, St Luke's Campus, Magdalen Road, Exeter, Devon, EX1 2LU, England.

Background: Postural hypotension (PH), the reduction in blood pressure when rising from sitting or lying 0to standing, is a risk factor for falls, cognitive decline and mortality. However, it is not often tested for in primary care. PH prevalence varies according to definition, population, care setting and measurement method. The aim of this study was to determine the prevalence of PH across different care settings and disease subgroups.

Methods: Systematic review, meta-analyses and meta-regression. We searched Medline and Embase to October 2019 for studies based in primary, community or institutional care settings reporting PH prevalence. Data and study level demographics were extracted independently by two reviewers. Pooled estimates for mean PH prevalence were compared between care settings and disease subgroups using random effects meta-analyses. Predictors of PH were explored using meta-regression. Quality assessment was undertaken using an adapted Newcastle-Ottawa Scale.

Results: One thousand eight hundred sixteen studies were identified; 61 contributed to analyses. Pooled prevalences for PH using the consensus definition were 17% (95% CI, 14-20%; I = 99%) for 34 community cohorts, 19% (15-25%; I = 98%) for 23 primary care cohorts and 31% (15-50%; I = 0%) for 3 residential care or nursing homes cohorts (P = 0.16 between groups). By condition, prevalences were 20% (16-23%; I = 98%) with hypertension (20 cohorts), 21% (16-26%; I = 92%) with diabetes (4 cohorts), 25% (18-33%; I = 88%) with Parkinson's disease (7 cohorts) and 29% (25-33%, I = 0%) with dementia (3 cohorts), compared to 14% (12-17%, I = 99%) without these conditions (P < 0.01 between groups). Multivariable meta-regression modelling identified increasing age and diabetes as predictors of PH (P < 0.01, P = 0.13, respectively; R = 36%). PH prevalence was not affected by blood pressure measurement device (P = 0.65) or sitting or supine resting position (P = 0.24), however, when the definition of PH did not fulfil the consensus description, but fell within its parameters, prevalence was underestimated (P = 0.01) irrespective of study quality (P = 0.04).

Conclusions: PH prevalence in populations relevant to primary care is substantial and the definition of PH used is important. Our findings emphasise the importance of considering checking for PH, particularly in vulnerable populations, to enable interventions to manage it. These data should contribute to future guidelines relevant to the detection and treatment of PH.

Prospero: CRD42017075423.
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http://dx.doi.org/10.1186/s12875-020-01313-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777418PMC
January 2021

Vitamin D and COVID-19 in older age: evidence versus expectations.

Br J Gen Pract 2021 01 28;71(702):10-11. Epub 2020 Dec 28.

Primary Care Research Group, Institute of Health Services Research, University of Exeter Medical School, Exeter.

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http://dx.doi.org/10.3399/bjgp21X714377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759342PMC
January 2021

Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.

Hypertension 2021 02 21;77(2):650-661. Epub 2020 Dec 21.

NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital and University of Exeter College of Medicine & Health, England (A.C.S.).

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803446PMC
February 2021

Tractographic and Microstructural Analysis of the Dentato-Rubro-Thalamo-Cortical Tracts in Children Using Diffusion MRI.

Cereb Cortex 2021 Mar;31(5):2595-2609

Developmental Imaging and Biophysics Section, UCL-GOS Institute of Child Health, London WC1N 1EH, UK.

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors.
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http://dx.doi.org/10.1093/cercor/bhaa377DOI Listing
March 2021

Randomized Clinical Trial of Inreach With or Without Mailed Outreach to Promote Hepatitis C Screening in a Difficult-to-Reach Patient Population.

Am J Gastroenterol 2021 05;116(5):976-983

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.

Introduction: Hepatitis C virus (HCV) treatment can significantly reduce the risk of liver-related mortality; however, many patients remain unaware of their infection in clinical practice. The aim of this study is to compare the effectiveness of inreach, with and without mailed outreach, to increase HCV screening and follow-up in a large, difficult-to-reach patient population.

Methods: We conducted a pragmatic randomized clinical trial from August 2018 to May 2019 in a large safety-net health system. Patients born between 1945 and 1965 were randomly assigned (1:1) to inreach with an electronic health record reminder to providers (n = 6,195) or inreach plus mailed HCV screening outreach (n = 6,191) to complete HCV antibody screening. Outreach also included processes to promote HCV RNA testing among those with a positive HCV antibody and linkage to care among those with positive HCV RNA. The primary outcome was completion of HCV antibody testing within 3 months of randomization (ClinicalTrials.gov NCT03706742).

Results: We included 12,386 eligible patients (median age 60 years; 46.5% Hispanic, 33.0% Black, and 16.0% White). In intent-to-treat analyses, HCV screening completion was significantly higher among inreach-plus-outreach patients than inreach-alone patients at 3 months (14.6% vs 7.4%, P < 0.001) and 6 months (17.4% vs 9.8%, P < 0.001) after randomization. Among those who completed HCV screening within 6 months, a higher proportion of inreach-plus-outreach patients with positive antibody results completed RNA testing within 3 months than inreach-alone patients (81.1% vs 57.1%, respectively, P = 0.02); however, linkage to care within 3 months of HCV infection confirmation did not significantly differ between the 2 groups (48.1% vs 75.0%, respectively, P = 0.24).

Discussion: Among difficult-to-reach patients, a combination of inreach and mailed outreach significantly increased HCV screening compared with inreach alone. However, HCV screening completion in both arms remained low, highlighting a need for more intensive interventions.
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http://dx.doi.org/10.14309/ajg.0000000000001085DOI Listing
May 2021

Neurosurgical applications of tractography in the UK.

Br J Neurosurg 2020 Dec 14:1-6. Epub 2020 Dec 14.

Developmental Imaging and Biophysics Section, UCL GOS Institute of Child Health, London, UK.

Introduction: Tractography derived from diffusion MRI can provide important insights into human brain microstructure . Neurosurgeons were quick to adopt the technique at the turn of the century, but it remains plagued by technical fallibilities. This study aims to describe how tractography is deployed clinically in a modern-day, public healthcare system, serving as a snapshot from the 'shop floor' of British neurosurgical practice.

Methods: An 11-question survey was circulated to the mailing lists of the Society of British Neurological Surgeons and British Neurosurgical Trainees' Association, including questions on frequency, indication, tracts reconstructed, specific details of techniques used and personnel by whom it was performed, and a free-text section on the limitations of tractography.

Results: 58 survey responses were received, covering all 40 neurosurgical units in the UK and Ireland. Overall, responses were received from neurosurgeons at 36 units (90.0%) stating tractography was in use at that unit. 74.1% of the responses were from Consultants. The most common indication for tractography was in tumour resection. It was most commonly performed by neuroradiologists or imaging scientists. 75.9% of respondents stated that the model used to process tractography was the diffusion tensor (DTI). Many respondents were unaware of which algorithm (74.1%) or software tools (65.6%) were used by the operator to produce tractography visualisations. The corticospinal tract was the most commonly reconstructed tract. The most commonly cited limitations of the technique were perceived inaccuracy and brain shift.

Conclusions: In this UK-based survey of practising neurosurgeons, we show that 90% of neurosurgical units in the UK and Ireland use tractography regularly; that predominantly DTI-based reconstructions are used; that tumour resection remains the most frequent use of the technique; and that large tracts such as the corticospinal tract are most frequently identified. Many neurosurgeons remain unfamiliar with the underlying methods used to produce tractography visualisations.
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http://dx.doi.org/10.1080/02688697.2020.1849542DOI Listing
December 2020
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