Publications by authors named "Peter Brown"

695 Publications

Bimodal Cambial Activity and False-Ring Formation in Conifers Under a Monsoon Climate.

Tree Physiol 2021 Apr 5. Epub 2021 Apr 5.

Laboratory of Tree-Ring Research, University of Arizona, Tucson, AZ 85721, USA.

Tracking wood formation in semi-arid regions during the seasonal march of precipitation extremes has two important applications. It can provide 1) insight into the adaptive capacities of trees to drought, and 2) a basis for a richer interpretation of tree-ring data, assisting in a deeper understanding of past and current climate. In the southwestern United States, the anatomical signature of seasonally bimodal precipitation is the 'false ring'-a band of latewood-like cells in the earlywood. These occur when a particularly deep drought during the early growing season ends abruptly with timely, mid-growing season monsoonal rains. Such conditions presented in southern Arizona in 2014, enabling us to explore false-ring formation in ponderosa pine (Pinus ponderosa) and Douglas-fir (Pseudotsuga menziesii) in mixed-conifer forest at 2573 m.a.s.l.. We ask: What were the cell-by-cell timings and durations in the phases of wood cell development in 2014? How do these seasonal patterns relate to strongly fluctuating environmental conditions during the growing season? We took weekly microcores from March through November from six ponderosa pine and seven Douglas-fir trees at a well-instrumented flux tower site. Thin sections were prepared and we counted cells in cambial, expansion, cell-wall-thickening and mature phases. For ponderosa pine trees forming a false ring, the first impact of intensifying seasonal drought was seen in the enlarging phase, and then, almost a month later, in cambial activity. In this species, recovery from drought was associated with recovery first in cambial activity, followed by cell enlargement. This timing raised the possibility that cell division may be affected by atmospheric moisture increases before soil recharge. In both species, the last false-ring cells matured during the summer rainy season. Bimodal cambial activity coincident with moisture availability was observed in both species, whether or not they formed a false ring. This deeper knowledge of the precise timing of both developmental and environmental events should help define mechanistic connections among these factors in creating bimodal growth patterns.
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http://dx.doi.org/10.1093/treephys/tpab045DOI Listing
April 2021

Predicting outcomes in anal cancer patients using multi-centre data and distributed learning - A proof-of-concept study.

Radiother Oncol 2021 Mar 20;159:183-189. Epub 2021 Mar 20.

Leeds Institute of Medical Research at St James's, University of Leeds, United Kingdom. Electronic address:

Background And Purpose: Predicting outcomes is challenging in rare cancers. Single-institutional datasets are often small and multi-institutional data sharing is complex. Distributed learning allows machine learning models to use data from multiple institutions without exchanging individual patient-level data. We demonstrate this technique in a proof-of-concept study of anal cancer patients treated with chemoradiotherapy across multiple European countries.

Materials And Methods: atomCAT is a three-centre collaboration between Leeds Cancer Centre (UK), MAASTRO Clinic (The Netherlands) and Oslo University Hospital (Norway). We trained and validated a Cox proportional hazards regression model in a distributed fashion using data from 281 patients treated with radical, conformal chemoradiotherapy for anal cancer in three institutions. Our primary endpoint was overall survival. We selected disease stage, sex, age, primary tumour size, and planned radiotherapy dose (in EQD2) a priori as predictor variables.

Results: The Cox regression model trained across all three centres found worse overall survival for high risk disease stage (HR = 2.02), male sex (HR = 3.06), older age (HR = 1.33 per 10 years), larger primary tumour volume (HR = 1.05 per 10 cm) and lower radiotherapy dose (HR = 1.20 per 5 Gy). A mean concordance index of 0.72 was achieved during validation, with limited variation between centres (Leeds = 0.72, MAASTRO = 0.74, Oslo = 0.70). The global model performed well for risk stratification for two out of three centres.

Conclusions: Using distributed learning, we accessed and analysed one of the largest available multi-institutional cohorts of anal cancer patients treated with modern radiotherapy techniques. This demonstrates the value of distributed learning in outcome modelling for rare cancers.
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http://dx.doi.org/10.1016/j.radonc.2021.03.013DOI Listing
March 2021

Probing the SAM Binding Site of SARS-CoV-2 nsp14 in vitro Using SAM Competitive Inhibitors Guides Developing Selective bi-substrate Inhibitors.

bioRxiv 2021 Feb 19. Epub 2021 Feb 19.

The COVID-19 pandemic has clearly brought the healthcare systems world-wide to a breaking point along with devastating socioeconomic consequences. The SARS-CoV-2 virus which causes the disease uses RNA capping to evade the human immune system. Non-structural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small molecule inhibitors of nsp14 methyltransferase (MT) activity, we developed and employed a radiometric MT assay to screen a library of 161 in house synthesized S-adenosylmethionine (SAM) competitive methyltransferase inhibitors and SAM analogs. Among seven identified screening hits, SS148 inhibited nsp14 MT activity with an IC value of 70 ± 6 nM and was selective against 20 human protein lysine methyltransferases indicating significant differences in SAM binding sites. Interestingly, DS0464 with IC value of 1.1 ± 0.2 μM showed a bi-substrate competitive inhibitor mechanism of action. Modeling the binding of this compound to nsp14 suggests that the terminal phenyl group extends into the RNA binding site. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein methyltransferases. The structure-activity relationship provided by these compounds should guide the optimization of selective bi-substrate nsp14 inhibitors and may provide a path towards a novel class of antivirals against COVID-19, and possibly other coronaviruses.
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http://dx.doi.org/10.1101/2021.02.19.424337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899450PMC
February 2021

A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6.

J Med Chem 2021 Apr 16;64(7):3697-3706. Epub 2021 Feb 16.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (SGC6870). is a potent PRMT6 inhibitor (IC = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6- complex and kinetic studies revealed binds a unique, induced allosteric pocket. Additionally, engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, 's enantiomer, (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, - is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035306PMC
April 2021

EEG measures of sensorimotor processing and their development are abnormal in children with isolated dystonia and dystonic cerebral palsy.

Neuroimage Clin 2021 Jan 19;30:102569. Epub 2021 Jan 19.

Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, London SE1 7EH, United Kingdom. Electronic address:

Dystonia is a disorder of sensorimotor integration associated with abnormal oscillatory activity within the basal ganglia-thalamo-cortical networks. Event-related changes in spectral EEG activity reflect cortical processing but are sparsely investigated in relation to sensorimotor processing in dystonia. This study investigates modulation of sensorimotor cortex EEG activity in response to a proprioceptive stimulus in children with dystonia and dystonic cerebral palsy (CP). Proprioceptive stimuli, comprising brief stretches of the wrist flexors, were delivered via a robotic wrist interface to 30 young people with dystonia (20 isolated genetic/idiopathic and 10 dystonic CP) and 22 controls (mean age 12.7 years). Scalp EEG was recorded using the 10-20 international system and the relative change in post-stimulus power with respect to baseline was calculated for the alpha (8-12 Hz) and beta (14-30 Hz) frequency bands. A clear developmental profile in event-related spectral changes was seen in controls. Controls showed a prominent early alpha/mu band event-related desynchronisation (ERD) followed by an event-related synchronisation (ERS) over the contralateral sensorimotor cortex following movement of either hand. The alpha ERD was significantly smaller in the dystonia groups for both dominant and non-dominant hand movement (ANCOVA across the 3 groups with age as covariate: dominant hand F(2,47) = 4.45 p = 0.017; non-dominant hand F(2,42) = 9.397 p < 0.001. Alpha ERS was significantly smaller in dystonia for the dominant hand (ANCOVA F(2,47) = 7.786 p = 0.001). There was no significant difference in ERD or ERS between genetic/idiopathic dystonia and dystonic CP. CONCLUSION: Modulation of alpha/mu activity by a proprioceptive stimulus is reduced in dystonia, demonstrating a developmental abnormality of sensorimotor processing which is common to isolated genetic/idiopathic and acquired dystonia/dystonic CP.
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http://dx.doi.org/10.1016/j.nicl.2021.102569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044718PMC
January 2021

Closed-Loop Deep Brain Stimulation for Essential Tremor Based on Thalamic Local Field Potentials.

Mov Disord 2021 Apr 6;36(4):863-873. Epub 2021 Feb 6.

MRC Brain Network Dynamics Unit, University of Oxford, Oxford, UK.

Background: High-frequency thalamic stimulation is an effective therapy for essential tremor, which mainly affects voluntary movements and/or sustained postures. However, continuous stimulation may deliver unnecessary current to the brain due to the intermittent nature of the tremor.

Objective: We proposed to close the loop of thalamic stimulation by detecting tremor-provoking movement states using local field potentials recorded from the same electrodes implanted for stimulation, so that the stimulation is only delivered when necessary.

Methods: Eight patients with essential tremor participated in this study. Patient-specific support vector machine classifiers were first trained using data recorded while the patient performed tremor-provoking movements. Then, the trained models were applied in real-time to detect these movements and triggered the delivery of stimulation.

Results: Using the proposed method, stimulation was switched on for 80.37 ± 7.06% of the time when tremor-evoking movements were present. In comparison, the stimulation was switched on for 12.71 ± 7.06% of the time when the patients were at rest and tremor-free. Compared with continuous stimulation, a similar amount of tremor suppression was achieved while only delivering 36.62 ± 13.49% of the energy used in continuous stimulation.

Conclusions: The results suggest that responsive thalamic stimulation for essential tremor based on tremor-provoking movement detection can be achieved without any requirement for external sensors or additional electrocorticography strips. Further research is required to investigate whether the decoding model is stable across time and generalizable to the variety of activities patients may engage with in everyday life. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610625PMC
April 2021

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.

J Med Chem 2021 02 1;64(3):1584-1592. Epub 2021 Feb 1.

Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.

Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist , which binds to the NSD2-PWWP1 domain with a of 3.4 μM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01768DOI Listing
February 2021

Cortical connectivity of the nucleus basalis of Meynert in Parkinson's disease and Lewy body dementias.

Brain 2021 Apr;144(3):781-788

Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, London, UK.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography with the spatial resolution of MRI tractography to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing deep brain stimulation of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: (i) a beta band network to supplementary motor area, where activity in this region was found to drive activity in the NBM; (ii) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus; and (iii) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function, respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.
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http://dx.doi.org/10.1093/brain/awaa411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041337PMC
April 2021

Computing conditional entropies for quantum correlations.

Nat Commun 2021 Jan 25;12(1):575. Epub 2021 Jan 25.

Univ Lyon, ENS Lyon, UCBL, CNRS, LIP, F-69342, Lyon, Cedex 07, France.

The rates of quantum cryptographic protocols are usually expressed in terms of a conditional entropy minimized over a certain set of quantum states. In particular, in the device-independent setting, the minimization is over all the quantum states jointly held by the adversary and the parties that are consistent with the statistics that are seen by the parties. Here, we introduce a method to approximate such entropic quantities. Applied to the setting of device-independent randomness generation and quantum key distribution, we obtain improvements on protocol rates in various settings. In particular, we find new upper bounds on the minimal global detection efficiency required to perform device-independent quantum key distribution without additional preprocessing. Furthermore, we show that our construction can be readily combined with the entropy accumulation theorem in order to establish full finite-key security proofs for these protocols.
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http://dx.doi.org/10.1038/s41467-020-20018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835250PMC
January 2021

Physiological Artifacts and the Implications for Brain-Machine-Interface Design.

Conf Proc IEEE Int Conf Syst Man Cybern 2020 Oct;2020:1498-1504

MRC Brain Network Dynamics Unit and Department of Engineering Science University of Oxford Oxford, UK.

The accurate measurement of brain activity by Brain-Machine-Interfaces (BMI) and closed-loop Deep Brain Stimulators (DBS) is one of the most important steps in communicating between the brain and subsequent processing blocks. In conventional chest-mounted systems, frequently used in DBS, a significant amount of artifact can be induced in the sensing interface, often as a common-mode signal applied between the case and the sensing electrodes. Attenuating this common-mode signal can be a serious challenge in these systems due to finite common-mode-rejection-ratio (CMRR) capability in the interface. Emerging BMI and DBS devices are being developed which can mount on the skull. Mounting the system on the cranial region can potentially suppress these induced physiological signals by limiting the artifact amplitude. In this study, we model the effect of artifacts by focusing on cardiac activity, using a current- source dipole model in a torso-shaped volume conductor. Performing finite element simulation with the different DBS architectures, we estimate the ECG common mode artifacts for several device architectures. Using this model helps define the overall requirements for the total system CMRR to maintain resolution of brain activity. The results of the simulations estimate that the cardiac artifacts for skull-mounted systems will have a significantly lower effect than non-cranial systems that include the pectoral region. It is expected that with a pectoral mounted device, a minimum of 60-80 dB CMRR is required to suppress the ECG artifact, depending on device placement relative to the cardiac dipole, while in cranially mounted devices, a 0 dB CMRR is sufficient, in the worst-case scenario. In addition, the model suggests existing commercial devices could optimize performance with a right-hand side placement. The methods used for estimating cardiac artifacts can be extended to other sources such as motion/muscle sources. The susceptibility of the device to artifacts has significant implications for the practical translation of closed-loop DBS and BMI, including the choice of biomarkers, the system design requirements, and the surgical placement of the device relative to artifact sources.
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http://dx.doi.org/10.1109/SMC42975.2020.9283328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116608PMC
October 2020

Identification of small molecule allosteric modulators of 5,10-methylenetetrahydrofolate reductase (MTHFR) by targeting its unique regulatory domain.

Biochimie 2021 Apr 18;183:100-107. Epub 2021 Jan 18.

Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, OX3 7DQ, UK. Electronic address:

The folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis. MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of AdoMet to an allosteric regulatory domain distal to the enzyme's active site, which we have previously identified to constitute a novel fold with a druggable pocket. Here, we screened 162 AdoMet mimetics using differential scanning fluorimetry, and identified 4 compounds that stabilized this regulatory domain. Three compounds were sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation was provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4). Using surface plasmon resonance, we confirmed that (S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with sub-micromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations. Combining binding assays, kinetic characterization and compound docking, this work indicates the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors.
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http://dx.doi.org/10.1016/j.biochi.2021.01.007DOI Listing
April 2021

Technology of deep brain stimulation: current status and future directions.

Nat Rev Neurol 2021 Feb 26;17(2):75-87. Epub 2020 Nov 26.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.
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http://dx.doi.org/10.1038/s41582-020-00426-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116699PMC
February 2021

Subthalamic beta-targeted neurofeedback speeds up movement initiation but increases tremor in Parkinsonian patients.

Elife 2020 11 18;9. Epub 2020 Nov 18.

MRC Brain Network Dynamics Unit at the University of Oxford, Oxford, United Kingdom.

Previous studies have explored neurofeedback training for Parkinsonian patients to suppress beta oscillations in the subthalamic nucleus (STN). However, its impacts on movements and Parkinsonian tremor are unclear. We developed a neurofeedback paradigm targeting STN beta bursts and investigated whether neurofeedback training could improve motor initiation in Parkinson's disease compared to passive observation. Our task additionally allowed us to test which endogenous changes in oscillatory STN activities are associated with trial-to-trial motor performance. Neurofeedback training reduced beta synchrony and increased gamma activity within the STN, and reduced beta band coupling between the STN and motor cortex. These changes were accompanied by reduced reaction times in subsequently cued movements. However, in Parkinsonian patients with pre-existing symptoms of tremor, successful volitional beta suppression was associated with an amplification of tremor which correlated with theta band activity in STN local field potentials, suggesting an additional cross-frequency interaction between STN beta and theta activities.
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http://dx.doi.org/10.7554/eLife.60979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695453PMC
November 2020

Cross-frequency coupling between gamma oscillations and deep brain stimulation frequency in Parkinson's disease.

Brain 2020 12;143(11):3393-3407

Section of Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson's disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson's disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.
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http://dx.doi.org/10.1093/brain/awaa297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116448PMC
December 2020

Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation.

J Neurosci 2020 11 21;40(46):8964-8972. Epub 2020 Oct 21.

MRC Brain Network Dynamics Unit, University of Oxford, Oxford OX1 3TH, United Kingdom

Patients with advanced Parkinson's can be treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of 10 Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of DBS strategies to ameliorate gait impairments. We tested whether the subthalamic nucleus (STN) in humans is causally involved in controlling stepping movements. To this end, we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation (DBS), as in these individuals we can stimulate the STNs in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS (altDBS) could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait.
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http://dx.doi.org/10.1523/JNEUROSCI.1767-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659462PMC
November 2020

Closed-loop DBS triggered by real-time movement and tremor decoding based on thalamic LFPs for essential tremor.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3602-3605

High frequency Deep Brain Stimulation (DBS) targeting the motor thalamus is an effective therapy for essential tremor (ET). However, since tremor mainly affects periods of voluntary movements and sustained postures in ET, conventional continuous stimulation may deliver unnecessary current to the brain. Here we tried to decode movement states based on local field potentials (LFPs) recorded from motor thalamus and zona incerta in real-time to trigger the switching on and off of DBS in three patients with ET. Patient-specific models were first identified using thalamic LFPs recorded while the patient performed movements that tended to trigger tremor in everyday life. During the real-time test, LFPs were continuously recorded to decode movements and tremor, and the detection triggered stimulation. Results show that voluntary movements can be detected with a mean sensitivity ranging from 76.8% to 88.6% and a false positive rate ranging from 16.0% to 23.1% Postural tremor was detected with similar accuracy. The closed-loop DBS triggered by tremor detection suppressed intention tremor by 90.5% with a false positive rate of 20.3%.Clinical Relevance- This is the first study on closed-loop DBS triggered by real-time movement and tremor decoding based solely on thalamic LFPs. The results suggest that responsive DBS based on movement and tremor detection can be achieved without any requirement for external sensors or additional electrocorticography strips.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116198PMC
July 2020

Artefact-free recording of local field potentials with simultaneous stimulation for closed-loop Deep-Brain Stimulation.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3367-3370

Continuous high frequency Deep Brain Stimulation (DBS) is a standard therapy for several neurological disorders. Closed-loop DBS is expected to further improve treatment by providing adaptive, on-demand therapy. Local field potentials (LFPs) recorded from the stimulation electrodes are the most often used feedback signal in closed-loop DBS. However, closed-loop DBS based on LFPs requires simultaneous recording and stimulating, which remains a challenge due to persistent stimulation artefacts that distort underlying LFP biomarkers. Here we first investigate the nature of the stimulation-induced artefacts and review several techniques that have been proposed to deal with them. Then we propose a new method to synchronize the sampling clock with the stimulation pulse so that the stimulation artefacts are never sampled, while at the same time the Nyquist-Shannon theorem is satisfied for uninterrupted LFP recording. Test results show that this method achieves true uninterrupted artefact-free LFP recording over a wide frequency band and for a wide range of stimulation frequencies.Clinical relevance-The method proposed here provides continuous and artefact-free recording of LFPs close to the stimulation target, and thereby facilitates the implementation of more advanced closed-loop DBS using LFPs as feedback.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116199PMC
July 2020

Optimizing Time-Frequency Feature Extraction and Channel Selection through Gradient Backpropagation to Improve Action Decoding based on Subthalamic Local Field Potentials.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3023-3026

Neural oscillating patterns, or time-frequency features, predicting voluntary motor intention, can be extracted from the local field potentials (LFPs) recorded from the sub-thalamic nucleus (STN) or thalamus of human patients implanted with deep brain stimulation (DBS) electrodes for the treatment of movement disorders. This paper investigates the optimization of signal conditioning processes using deep learning to augment time-frequency feature extraction from LFP signals, with the aim of improving the performance of real-time decoding of voluntary motor states. A brain-computer interface (BCI) pipeline capable of continuously classifying discrete pinch grip states from LFPs was designed in Pytorch, a deep learning framework. The pipeline was implemented offline on LFPs recorded from 5 different patients bilaterally implanted with DBS electrodes. Optimizing channel combination in different frequency bands and frequency domain feature extraction demonstrated improved classification accuracy of pinch grip detection and laterality of the pinch (either pinch of the left hand or pinch of the right hand). Overall, the optimized BCI pipeline achieved a maximal average classification accuracy of 79.67±10.02% when detecting all pinches and 67.06±10.14% when considering the laterality of the pinch.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116197PMC
July 2020

ECLIPSE utilizing gradient-modulated offset-independent adiabaticity (GOIA) pulses for highly selective human brain proton MRSI.

NMR Biomed 2021 01 1;34(1):e4415. Epub 2020 Oct 1.

Department of Radiology and Biomedical Imaging, Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, 06520, USA.

A multitude of extracranial lipid suppression methods exist for proton MRSI acquisitions. Popular and emerging lipid suppression methods each have their inherent set of advantages and disadvantages related to the achievable level of lipid suppression, RF power deposition, insensitivity to B field and lipid T heterogeneity, brain coverage, spatial selectivity, chemical shift displacement (CSD) errors and the reliability of spectroscopic data spanning the observed 0.9-4.7 ppm band. The utility of elliptical localization with pulsed second order fields (ECLIPSE) was previously demonstrated with a greater than 100-fold in extracranial lipid suppression and low power requirements utilizing 3 kHz bandwidth AFP pulses. Like all gradient-based localization methods, ECLIPSE is sensitive to CSD errors, resulting in a modified metabolic profile in edge-of-ROI voxels. In this work, ECLIPSE is extended with 15 kHz bandwidth second order gradient-modulated RF pulses based on the gradient offset-independent adiabaticity (GOIA) algorithm to greatly reduce CSD and improve spatial selectivity. An adiabatic double spin-echo ECLIPSE inner volume selection (TE = 45 ms) MRSI method and an ECLIPSE outer volume suppression (TE = 3.2 ms) FID-MRSI method were implemented. Both GOIA-ECLIPSE MRSI sequences provided artifact-free metabolite spectra in vivo, with a greater than 100-fold in lipid suppression and less than 2.6 mm in-plane CSD and less than 3.3 mm transition width for edge-of-ROI voxels, representing an ~5-fold improvement compared with the parent, nongradient-modulated method. Despite the 5-fold larger bandwidth, GOIA-ECLIPSE only required a 1.9-fold increase in RF power. The highly robust lipid suppression combined with low CSD and sharp ROI edge transitions make GOIA-ECLIPSE an attractive alternative to commonly employed lipid suppression methods. Furthermore, the low RF power deposition demonstrates that GOIA-ECLIPSE is very well suited for high field (≥3 T) MRSI applications.
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http://dx.doi.org/10.1002/nbm.4415DOI Listing
January 2021

A flow resistive inspiratory muscle training mask worn during high-intensity interval training does not improve 5 km running time-trial performance.

Eur J Appl Physiol 2021 Jan 1;121(1):183-191. Epub 2020 Oct 1.

Physical Activity, Public Health and Wellness Research Group, Sheffield Hallam University, Sheffield, UK.

Purpose: There is little evidence of the ergogenic effect of flow-resistive masks worn during exercise. We compared a flow-resistive face mask (MASK) worn during high-intensity interval training (HIIT) against pressure threshold loading inspiratory muscle training (IMT).

Methods: 23 participants (13 males) completed a 5 km time trial and six weeks of HIIT (3 sessions weekly). HIIT (n = 8) consisted of repeated work (2 min) at the speed equivalent to 95% [Formula: see text]O peak with equal rest. Repetitions were incremental (six in weeks 1, 2 and 6, eight in weeks 3 and 4 and ten in week 5). Participants were allocated to one of three training groups. MASK (n = 8) wore a flow-resistive mask during all sessions. The IMT group (n = 8) completed 2 × 30 breaths daily at 50% maximum inspiratory pressure (P). A control group (CON, n = 7) completed HIIT only. Following HIIT, participants completed two 5 km time trials, the first matched identically to pre-intervention trial (ISO time), and a self-paced effort.

Results: Time trial performance was improved in all groups (MASK 3.1 ± 1.7%, IMT, 5.7 ± 1.5% and CON 2.6 ± 1.0%, p < 0.05). IMT improved greater than MASK and CON (p = 0.004). Post intervention, P and diaphragm thickness were improved in IMT only (32% and 9.5%, respectively, p = 0.003 and 0.024).

Conclusion: A flow-resistive mask worn during HIIT provides no benefit to 5 km performance when compared to HIIT only. Supplementing HIIT with IMT improves respiratory muscle strength, morphology and performance greater than HIIT alone.
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http://dx.doi.org/10.1007/s00421-020-04505-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815609PMC
January 2021

Parkinson's disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo.

Neurobiol Dis 2020 12 28;146:105119. Epub 2020 Sep 28.

Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK. Electronic address:

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.
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http://dx.doi.org/10.1016/j.nbd.2020.105119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710979PMC
December 2020

Arbitrarily Many Independent Observers Can Share the Nonlocality of a Single Maximally Entangled Qubit Pair.

Phys Rev Lett 2020 Aug;125(9):090401

Department of Mathematics, University of York, Heslington, York, YO10 5DD, United Kingdom.

Alice and Bob each have half of a pair of entangled qubits. Bob measures his half and then passes his qubit to a second Bob who measures again and so on. The goal is to maximize the number of Bobs that can have an expected violation of the Clauser-Horne-Shimony-Holt (CHSH) Bell inequality with the single Alice. This scenario was introduced in [R. Silva et al., Phys. Rev. Lett. 114, 250401 (2015)PRLTAO0031-900710.1103/PhysRevLett.114.250401] where the authors mentioned evidence that when the Bobs act independently and with unbiased inputs then at most two of them can expect to violate the CHSH inequality with Alice. Here we show that, contrary to this evidence, arbitrarily many independent Bobs can have an expected CHSH violation with the single Alice. Our proof is constructive and our measurement strategies can be generalized to work with a larger class of two-qubit states that includes all pure entangled two-qubit states. Since violation of a Bell inequality is necessary for device-independent tasks, our work represents a step towards an eventual understanding of the limitations on how much device-independent randomness can be robustly generated from a single pair of qubits.
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http://dx.doi.org/10.1103/PhysRevLett.125.090401DOI Listing
August 2020

Application of Machine Learning Using Decision Trees for Prognosis of Deep Brain Stimulation of Globus Pallidus Internus for Children With Dystonia.

Front Neurol 2020 Aug;11:825

Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

Background: While Deep Brain Stimulation (DBS) of the Globus pallidus internus is a well-established therapy for idiopathic/genetic dystonia, benefits for acquired dystonia are varied, ranging from modest improvement to deterioration. Predictive biomarkers to aid DBS prognosis for children are lacking, especially in acquired dystonias, such as dystonic Cerebral Palsy. We explored the potential role of machine learning techniques to identify parameters that could help predict DBS outcome.

Methods: We conducted a retrospective study of 244 children attending King's College Hospital between September 2007 and June 2018 for neurophysiological tests as part of their assessment for possible DBS at Evelina London Children's Hospital. For the 133 individuals who underwent DBS and had 1-year outcome data available, we assessed the potential predictive value of six patient parameters: sex, etiology (including cerebral palsy), baseline severity (Burke-Fahn-Marsden Dystonia Rating Scale-motor score), cranial MRI and two neurophysiological tests, Central Motor Conduction Time (CMCT) and Somatosensory Evoked Potential (SEP). We applied machine learning analysis to determine the best combination of these features to aid DBS prognosis. We developed a classification algorithm based on Decision Trees (DTs) with k-fold cross validation for independent testing. We analyzed all possible combinations of the six features and focused on acquired dystonias.

Results: Several trees resulted in better accuracy than the majority class classifier. However, the two features that consistently appeared in top 10 DTs were CMCT and baseline dystonia severity. A decision tree based on CMCT and baseline severity provided a range of sensitivity and specificity, depending on the threshold chosen for baseline dystonia severity. In situations where CMCT was not available, a DT using SEP alone provided better than the majority class classifier accuracy.

Conclusion: The results suggest that neurophysiological parameters can help predict DBS outcomes, and DTs provide a data-driven, highly interpretable decision support tool that lends itself to being used in clinical practice to help predict potential benefit of DBS in dystonic children. Our results encourage the introduction of neurophysiological parameters in assessment pathways, and data collection to facilitate multi-center evaluation and validation of these potential predictive markers and of the illustrative decision support tools presented here.
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http://dx.doi.org/10.3389/fneur.2020.00825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115974PMC
August 2020

Association of specific biotypes in patients with Parkinson disease and disease progression.

Neurology 2020 09 14;95(11):e1445-e1460. Epub 2020 Aug 14.

From the Institute of Science and Technology for Brain-inspired Intelligence (L.W., W.C., E.R., F.D, W.G., J. D., W.Z., S.W., J.F.), Fudan University; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (L.W., W.C., J. D., W.Z., S.W., J.F.) (Fudan University), Ministry of Education, Shanghai, China; Department of Computer Science (E.R., J.F.), University of Warwick, Coventry; Oxford Centre for Computational Neuroscience (E.R.), UK; Department of Neurology and National Clinical Research Center for Aging and Medicine (F.L., J.W.), Huashan Hospital, Fudan University, Shanghai, China; and Medical Research Council Brain Network Dynamics Unit (P.B.) and Nuffield Department of Clinical Neurosciences (P.B.), University of Oxford, UK.

Objective: To identify biotypes in patients with newly diagnosed Parkinson disease (PD) and to test whether these biotypes could explain interindividual differences in longitudinal progression.

Methods: In this longitudinal analysis, we use a data-driven approach clustering PD patients from the Parkinson's Progression Markers Initiative (n = 314, age 61.0 ± 9.5, years 34.1% female, 5 years of follow-up). Voxel-level neuroanatomic features were estimated with deformation-based morphometry (DBM) of T1-weighted MRI. Voxels with deformation values that were significantly correlated ( < 0.01) with clinical scores (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Parts I-III and total score, tremor score, and postural instability and gait difficulty score) at baseline were selected. Then, these neuroanatomic features were subjected to hierarchical cluster analysis. Changes in the longitudinal progression and neuroanatomic pattern were compared between different biotypes.

Results: Two neuroanatomic biotypes were identified: biotype 1 (n = 114) with subcortical brain volumes smaller than heathy controls and biotype 2 (n = 200) with subcortical brain volumes larger than heathy controls. Biotype 1 had more severe motor impairment, autonomic dysfunction, and much worse REM sleep behavior disorder than biotype 2 at baseline. Although disease durations at the initial visit and follow-up were similar between biotypes, patients with PD with smaller subcortical brain volume had poorer prognosis, with more rapid decline in several clinical domains and in dopamine functional neuroimaging over an average of 5 years.

Conclusion: Robust neuroanatomic biotypes exist in PD with distinct clinical and neuroanatomic patterns. These biotypes can be detected at diagnosis and predict the course of longitudinal progression, which should benefit trial design and evaluation.
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http://dx.doi.org/10.1212/WNL.0000000000010498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116258PMC
September 2020

Acute effects of adaptive Deep Brain Stimulation in Parkinson's disease.

Brain Stimul 2020 Nov - Dec;13(6):1507-1516. Epub 2020 Jul 29.

Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, Amsterdam, The Netherlans. Electronic address:

Background: Beta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson's disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed.

Methods: To determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson's Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT).

Results: Mean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p = .001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p = .002), and did not achieve significance during cDBS (p = .08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p = .009), but not in aDBS (p = .407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS.

Conclusion: Beta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy.
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http://dx.doi.org/10.1016/j.brs.2020.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116216PMC
March 2021

Waveform changes with the evolution of beta bursts in the human subthalamic nucleus.

Clin Neurophysiol 2020 Sep 29;131(9):2086-2099. Epub 2020 Jun 29.

MRC Brain Network Dynamics Unit, University of Oxford, Oxford OX1 3TH, United Kingdom; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom.

Objective: Phasic bursts of beta band synchronisation have been linked to motor impairment in Parkinson's disease (PD). However, little is known about what terminates bursts.

Methods: We used the Hilbert-Huang transform to investigate beta bursts in the local field potential recorded from the subthalamic nucleus in nine patients with PD on and off levodopa.

Results: The sharpness of the beta waveform extrema fell as burst amplitude dropped. Conversely, an index of phase slips between waveform extrema, and the power of concurrent theta activity increased as burst amplitude fell. Theta activity was also increased on levodopa when beta bursts were attenuated. These phenomena were associated with reduction in coupling between beta phase and high gamma activity amplitude. We discuss how these findings may suggest that beta burst termination is associated with relative desynchronization of the beta drive, increase in competing theta activity and increased phase slips in the beta activity.

Conclusions: We characterise the dynamical nature of beta bursts, thereby permitting inferences about underlying activities and, in particular, about why bursts terminate.

Significance: Understanding the dynamical nature of beta bursts may help point to interventions that can cause their termination and potentially treat motor impairment in PD.
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http://dx.doi.org/10.1016/j.clinph.2020.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115847PMC
September 2020

Erratum to: Large expert-curated database for benchmarking document similarity detection in biomedical literature search.

Database (Oxford) 2020 01;2020

School of Information and Communication Technology, Griffith University, Gold Coast, QLD, Australia.

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http://dx.doi.org/10.1093/database/baz138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368162PMC
January 2020

Oil red O staining for lipid-laden macrophage index of bronchoalveolar lavage: interobserver agreement and challenges to interpretation.

J Am Soc Cytopathol 2020 Nov - Dec;9(6):563-569. Epub 2020 Jun 10.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Introduction: Oil Red O (ORO) staining on cytologic specimens with calculation of the lipid-laden macrophage index (LLMI) is used as a part of the workup in a number of clinical settings, particularly when aspiration is of concern. As a part of ongoing internal quality improvement measures, the objective of the present study was to evaluate the interobserver agreement of the LLMI calculation and to identify factors that affect the variability of the calculation.

Materials And Methods: There were 9 study participants, which included 3 trainees, 3 cytotechnologists, and 3 cytopathologists. Each participant reviewed 100 ORO-stained bronchoalveolar lavage slides and assigned an LLMI score to each case. The scores were categorized into 3 groups according to the associated aspiration risk: low, LLMI <40; intermediate, LLMI 40 to 90; and high, LLMI >90. The participants were also requested to note any challenges to the calculation for each case.

Results: The interobserver agreement among all participants was fair (κ = 0.23). Stratified by participant group, the interobserver agreement among the trainees was fair (κ = 0.24), among cytotechnologists was fair (κ = 0.32), and among cytopathologists was moderate (κ = 0.60). In 70 cases, at least one participant scored the case at least one category higher than the other participants; in 47 cases there was a two category difference. A primary diagnostic challenge reported by participants was macrophage pigmentation (hemosiderin, anthracosis).

Conclusions: We found only fair interobserver agreement among all 9 participants in the study. Hemosiderin and anthracotic pigmentation was a major factor impeding LLMI calculation resulting in overestimation of the LLMI.
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http://dx.doi.org/10.1016/j.jasc.2020.05.010DOI Listing
June 2020

Child undernutrition in households with microbiologically safer drinking water and 'improved water' in Tanna, Vanuatu.

J Water Health 2020 Jun;18(3):416-429

Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand E-mail: Public Health Unit, Southern District Health Board, Dunedin, New Zealand.

The Sustainable Development Goal drinking water indicators include microbiological safety measures, whereas the Millennium Development Goal indicator 'improved water' may be microbiologically unsafe. In rural Vanuatu, we undertook household surveys, child anthropometry, and tested stored drinking water, to investigate relationships between water and undernutrition. Using Escherichia coli most probable number, we categorized results according to Compartment Bag Test drinking water cutoffs: <1/100 mL (safe), 1-10/100 mL (intermediate risk), >10-100/100 mL (high risk), and >100/100 mL (very high risk). Of 201 households, 191 (95%) had microbiologically unsafe drinking water, regardless of 'improved' status. We investigated cross-sectional associations between households with microbiologically safer drinking water (≤10 E. coli/100 mL) versus 'improved water' and undernutrition among children. Of children under 5, 145 (48.8%, 95% CI: 42.8, 54.8) were stunted and 59 (19.1%, 95% CI: 14.4, 23.8) were underweight. Among households with 'improved water', the adjusted prevalence ratio (95% CI) of stunting was 0.61 (0.46, 0.80) and underweight was 0.46 (0.29, 0.73) compared with 'unimproved water'. However, we found no association between having drinking water with ≤10 E. coli/100 mL at one point in time and undernutrition. Longer-term variations in water quality and unmeasured conditions beyond water may have contributed to these associations.
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http://dx.doi.org/10.2166/wh.2020.262DOI Listing
June 2020