Publications by authors named "Mark Roberts"

405 Publications

Impact of Procedural Sedation on the Clinical Outcome of Microelectrode Recording Guided Deep Brain Stimulation in Patients with Parkinson's Disease.

J Clin Med 2021 Apr 7;10(8). Epub 2021 Apr 7.

Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a routine treatment of advanced Parkinson's disease (PD). DBS surgery is commonly performed under local anesthesia (LA) to obtain reliable microelectrode recordings. However, procedural sedation and/or analgesia (PSA) is often desirable to improve patient comfort. The impact of PSA in addition to LA on outcome is largely unknown. Therefore, we performed an observational study to assess the effect of PSA compared to LA alone during STN DBS surgery on outcome in PD patients.

Methods: Seventy PD patients (22 under LA, 48 under LA + PSA) scheduled for STN DBS implantation were included. Dexmedetomidine, clonidine or remifentanil were used for PSA. The primary outcome was the change in Movement Disorders Society Unified Parkinson's Disease Rating Score III (MDS-UPDRS III) and levodopa equivalent daily dosage (LEDD) between baseline, one month before surgery, and twelve months postoperatively. Secondary outcome measures were motor function during activities of daily living (MDS-UPDRS II), cognitive alterations and surgical adverse events. Postoperative assessment was conducted in "on" stimulation and "on" medication conditions.

Results: At twelve months follow-up, UPDRS III and UPDRS II scores in "on" medication conditions were similar between the LA and PSA groups. The two groups showed a similar LEDD reduction and an equivalent decline in executive function measured by the Stroop Color-Word Test, Trail Making Test-B, and verbal fluency. The incidence of perioperative and postoperative adverse events was similar between groups.

Conclusion: This study demonstrates that PSA during STN DBS implantation surgery in PD patients was not associated with differences in motor and non-motor outcome after twelve months compared with LA only.
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http://dx.doi.org/10.3390/jcm10081557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068017PMC
April 2021

Transcriptome and Functions of Granulocytic Myeloid-Derived Suppressor Cells Determine their Association with Disease Severity of COVID-19.

medRxiv 2021 Mar 29. Epub 2021 Mar 29.

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19, that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of Granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1 G-MDSC (Arg G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.
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http://dx.doi.org/10.1101/2021.03.26.21254441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010749PMC
March 2021

Are there common walking gait characteristics in patients diagnosed with late-onset Pompe disease?

Hum Mov Sci 2021 Mar 14;77:102777. Epub 2021 Mar 14.

Human Movement and Rehabilitation, School of Health and Society, University of Salford, Salford, UK.

Late-onset Pompe disease (LOPD) is a rare disease, defined as a progressive accumulation of lysosomal glycogen resulting in muscle weakness and respiratory problems. Anecdotally, individuals often have difficulties walking, yet, there is no three-dimensional data supporting these claims. We aimed to assess walking patterns in individuals with LOPD and compare with healthy individuals. Kinematic, kinetic and spatiotemporal data were compared during walking at a self-selected speed between individuals with LOPD (n = 12) and healthy controls (n = 12). Gait profile scores and movement analysis profiles were also determined to indicate gait quality. In comparison with healthy individuals, the LOPD group demonstrated greater thoracic sway (96%), hip adduction angles (56%) and pelvic range of motion (77%) and reduced hip extensor moments (36%). Greater group variance for the LOPD group were also observed. Individuals with LOPD had a slower (15%) walking speed and reduced cadence (7%). Gait profile scores were 37% greater in the LOPD group compared to the healthy group. Proximal muscular weakness associated with LOPD disease is likely to have resulted in a myopathic gait pattern, slower selected walking speeds and deviations in gait patterns. Although individuals with LOPD presented with some common characteristics, greater variability in gait patterns is likely to be a result of wide variability in phenotype spectrum observed with LOPD. This is the first study to examine walking in individuals with LOPD using instrumented gait analysis and provides an understanding of LOPD on walking function which can help orientate physiotherapy treatment for individuals with LOPD.
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http://dx.doi.org/10.1016/j.humov.2021.102777DOI Listing
March 2021

Prescriber perspectives on low-value prescribing: A qualitative study.

J Am Geriatr Soc 2021 Mar 12. Epub 2021 Mar 12.

Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Background: Health systems are increasingly implementing interventions to reduce older patients' use of low-value medications. However, prescribers' perspectives on medication value and the acceptability of interventions to reduce low-value prescribing are poorly understood.

Objective: To identify the characteristics that affect the value of a medication and those factors influencing low-value prescribing from the perspective of primary care physicians.

Design: Qualitative study using semi-structured interviews.

Setting: Academic and community primary care practices within University of Pittsburgh Medical Center health system.

Participants: Sixteen primary care physicians.

Measurements: We elicited 16 prescribers' perspectives on definitions and examples of low-value prescribing in older adults, the factors that incentivize them to engage in such prescribing, and the characteristics of interventions that would make them less likely to engage in low-value prescribing.

Results: We identified three key themes. First, prescribers viewed low-value prescribing among older adults as common, characterized both by features of the medications themselves and of the particular patients to whom they were prescribed. Second, prescribers described the causes of low-value prescribing as multifactorial, with factors related to patients, prescribers, and the health system as a whole, making low-value prescribing a default practice pattern. Third, interventions addressing low-value prescribing must minimize the cognitive load and time pressures that make low-value prescribing common. Interventions increasing time pressure or cognitive load, such as increased documentation, were considered less acceptable.

Conclusions: Our findings demonstrate that low-value prescribing is a well-recognized phenomenon, and that interventions to reduce low-value prescribing must consider physicians' perspectives and address the specific patient, prescriber and health system factors that make low-value prescribing a default practice.
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http://dx.doi.org/10.1111/jgs.17099DOI Listing
March 2021

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

EMBO Mol Med 2021 Apr 11;13(4):e13390. Epub 2021 Mar 11.

Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8 T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen-specific CD8 T-cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced effector CD8 T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen-specific CD8 T-cell killing, which has wide-ranging implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines.
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http://dx.doi.org/10.15252/emmm.202013390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033512PMC
April 2021

Presence of antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 in COVID-19 plasma.

PLoS One 2021 4;16(3):e0247640. Epub 2021 Mar 4.

Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, United States of America.

Background: Neutralizing-antibody (nAb) is the major focus of most ongoing COVID-19 vaccine trials. However, nAb response against SARS-CoV-2, when present, decays rapidly. Given the myriad roles of antibodies in immune responses, it is possible that antibodies could also mediate protection against SARS-CoV-2 via effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), which we sought to explore here.

Methods: Plasma of 3 uninfected controls and 20 subjects exposed to, or recovering from, SARS-CoV-2 infection were collected from U.S. and sub-Saharan Africa. Immunofluorescence assay was used to detect the presence of SARS-CoV-2 specific IgG antibodies in the plasma samples. SARS-CoV-2 specific neutralizing capability of these plasmas was assessed with SARS-CoV-2 spike pseudotyped virus. ADCC activity was assessed with a calcein release assay.

Results: SARS-CoV-2 specific IgG antibodies were detected in all COVID-19 subjects studied. All but three COVID-19 subjects contained nAb at high potency (>80% neutralization). Plasma from 19/20 of COVID-19 subjects also demonstrated strong ADCC activity against SARS-CoV-2 spike glycoprotein, including two individuals without nAb against SARS-CoV-2.

Conclusion: Both neutralizing and non-neutralizing COVID-19 plasmas can mediate ADCC. Our findings argue that evaluation of potential vaccines against SARS-CoV-2 should include investigation of the magnitude and durability of ADCC, in addition to nAb.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247640PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932539PMC
March 2021

Use of fibrinolytics and deoxyribonuclease in adult patients with pleural empyema: a consensus statement.

Lancet Respir Med 2021 Feb 2. Epub 2021 Feb 2.

Oxford Respiratory Trials Unit, University of Oxford, Oxford, UK.

Although our understanding of the pathogenesis of empyema has grown tremendously over the past few decades, questions still remain on how to optimally manage this condition. It has been almost a decade since the publication of the MIST2 trial, but there is still an extensive debate on the appropriate use of intrapleural fibrinolytic and deoxyribonuclease therapy in patients with empyema. Given the scarcity of overall guidance on this subject, we convened an international group of 22 experts from 20 institutions across five countries with experience and expertise in managing adult patients with empyema. We did a literature and internet search for reports addressing 11 clinically relevant questions pertaining to the use of intrapleural fibrinolytic and deoxyribonuclease therapy in adult patients with bacterial empyema. This Position Paper, consisting of seven graded and four ungraded recommendations, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience when necessary. Panel members participated in the development of the final recommendations using the modified Delphi technique. Our Position Paper aims to address the existing gap in knowledge and to provide consensus-based recommendations to offer guidance in clinical decision making when considering the use of intrapleural therapy in adult patients with bacterial empyema.
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http://dx.doi.org/10.1016/S2213-2600(20)30533-6DOI Listing
February 2021

Empirically constrained network models for contrast-dependent modulation of gamma rhythm in V1.

Neuroimage 2021 04 15;229:117748. Epub 2021 Jan 15.

Medical School, University of Nicosia, Nicosia 2408, Cyprus. Electronic address:

Gamma oscillations are thought to play a key role in neuronal network function and neuronal communication, yet the underlying generating mechanisms have not been fully elucidated to date. At least partly, this may be due to the fact that even in simple network models of interconnected inhibitory (I) and excitatory (E) neurons, many parameters remain unknown and are set based on practical considerations or by convention. Here, we mitigate this problem by requiring PING (Pyramidal Interneuron Network Gamma) models to simultaneously satisfy a broad set of criteria for realistic behaviour based on empirical data spanning both the single unit (spikes) and local population (LFP) levels while unknown parameters are varied. By doing so, we were able to constrain the parameter ranges and select empirically valid models. The derived model constraints implied weak rather than strong PING as the generating mechanism for gamma, connectivity between E and I neurons within specific bounds, and variations of the external input to E but not I neurons. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. Using an empirically-validated model we studied the route to gamma instability at high contrasts. This involved increased heterogeneity of E neurons with increasing input triggering a breakdown of I neuron pacemaker function. Further, we illustrate the model's capacity to resolve disputes in the literature concerning gamma oscillation properties and GABA conductance proxies. We propose that the models derived in our study will be useful for other modelling studies, and that our approach to the empirical constraining of PING models can be expanded when richer empirical datasets become available. As local gamma networks are the building blocks of larger networks that aim to understand complex cognition through their interactions, there is considerable value in improving our models of these building blocks.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117748DOI Listing
April 2021

Are Discount Rates Too High? Population Health and Intergenerational Equity.

Med Decis Making 2021 02 13;41(2):245-249. Epub 2021 Jan 13.

Department of Health Policy and Management, University of Pittsburgh Public Health, Pittsburgh, PA, USA.

Increasing attention is being paid to policy decisions in which shorter-term benefits may be eclipsed by longer-term harms, such as environmental damage. Health policy decisions have largely been spared this scrutiny, even though they too may contribute to longer-term harms. Any healthy population or society must sustain itself through reproduction, and therefore, transgenerational outcomes should be of intrinsic importance from a societal perspective. Yet, the discount rates typically employed in cost-effectiveness analyses have the effect of minimizing the importance of transgenerational health outcomes. We argue that, because cost-effectiveness analysis is based on foundational axioms of decision theory, it should value transgenerational outcomes consistently with those axioms, which require discount rates substantially lower than 3%. We discuss why such lower rates may not violate the Cretin-Keeler paradox.
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http://dx.doi.org/10.1177/0272989X20979816DOI Listing
February 2021

Combining Gamma With Alpha and Beta Power Modulation for Enhanced Cortical Mapping in Patients With Focal Epilepsy.

Front Hum Neurosci 2020 21;14:555054. Epub 2020 Dec 21.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands.

About one third of patients with epilepsy have seizures refractory to the medical treatment. Electrical stimulation mapping (ESM) is the gold standard for the identification of "eloquent" areas prior to resection of epileptogenic tissue. However, it is time-consuming and may cause undesired side effects. Broadband gamma activity (55-200 Hz) recorded with extraoperative electrocorticography (ECoG) during cognitive tasks may be an alternative to ESM but until now has not proven of definitive clinical value. Considering their role in cognition, the alpha (8-12 Hz) and beta (15-25 Hz) bands could further improve the identification of eloquent cortex. We compared gamma, alpha and beta activity, and their combinations for the identification of eloquent cortical areas defined by ESM. Ten patients with intractable focal epilepsy (age: 35.9 ± 9.1 years, range: 22-48, 8 females, 9 right handed) participated in a delayed-match-to-sample task, where syllable sounds were compared to visually presented letters. We used a generalized linear model (GLM) approach to find the optimal weighting of each band for predicting ESM-defined categories and estimated the diagnostic ability by calculating the area under the receiver operating characteristic (ROC) curve. Gamma activity increased more in eloquent than in non-eloquent areas, whereas alpha and beta power decreased more in eloquent areas. Diagnostic ability of each band was close to 0.7 for all bands but depended on multiple factors including the time period of the cognitive task, the location of the electrodes and the patient's degree of attention to the stimulus. We show that diagnostic ability can be increased by 3-5% by combining gamma and alpha and by 7.5-11% when gamma and beta were combined. We then show how ECoG power modulation from cognitive testing can be used to map the probability of eloquence in individual patients and how this probability map can be used in clinical settings to optimize ESM planning. We conclude that the combination of gamma and beta power modulation during cognitive testing can contribute to the identification of eloquent areas prior to ESM in patients with refractory focal epilepsy.
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http://dx.doi.org/10.3389/fnhum.2020.555054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779799PMC
December 2020

Noise-induced neurophysiological alterations in the rat medial geniculate body and thalamocortical desynchronization by deep brain stimulation.

J Neurophysiol 2021 02 6;125(2):661-671. Epub 2021 Jan 6.

School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

The thalamic medial geniculate body (MGB) is uniquely positioned within the neural tinnitus networks. Deep brain stimulation (DBS) of the MGB has been proposed as a possible novel treatment for tinnitus, yet mechanisms remain elusive. The aim of this study was to characterize neurophysiologic hallmarks in the MGB after noise exposure and to assess the neurophysiological effects of electrical stimulation of the MGB. Fourteen male Sprague-Dawley rats were included. Nine subjects were unilaterally exposed to a 16-kHz octave-band noise at 115 dB for 90 min, five received sham exposure. Single units were recorded from the contralateral MGB where spontaneous firing, coefficient of variation, response type, rate-level functions, and thresholds were determined. Local field potentials and electroencephalographical (EEG) recordings were performed before and after high-frequency DBS of the MGB. Thalamocortical synchronization and power were analyzed. In total, 214 single units were identified ( = 145 in noise-exposed group, = 69 in control group). After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous rate, whereas sustained- and suppressed-type neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. MGB DBS suppressed thalamocortical synchronization in the β and γ bands, supporting suppression of thalamocortical synchronization as an underlying mechanism of tinnitus suppression by high frequency DBS. These findings contribute to our understanding of the neurophysiologic consequences of noise exposure and the mechanism of potential DBS therapy for tinnitus. Separate functional classes of MGB neurons might have distinct roles in tinnitus pathophysiology. After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous firing, whereas sustained and suppressed neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. Furthermore, results suggest desynchronization of thalamocortical β and γ oscillations as a mechanism of tinnitus suppression by MGB DBS.
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http://dx.doi.org/10.1152/jn.00752.2019DOI Listing
February 2021

Ambulatory management of secondary spontaneous pneumothorax: a randomised controlled trial.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Academic Respiratory Unit Bristol, Westbury on Trym, United Kingdom.

Objective: Secondary spontaneous pneumothorax (SSP) is traditionally managed with an intercostal chest tube attached to an underwater seal. We investigated whether use of a one-way flutter valve shortened length of patients' stay (LoS).

Methods: This open-label randomised controlled trial enrolled patients presenting with SSP and randomised to either a chest tube and underwater seal (standard care: SC) or ambulatory care (AC) with a flutter valve. The type of flutter valve used depended on whether at randomisation the patient already had a chest tube in place: in those without a chest tube a Pleural Vent (PV) was used; in those with a chest tube in situ, an Atrium Pneumostat (AP) valve was attached. The primary end-point was LoS.

Results: Between March 2017 and March 2020, 41 patients underwent randomisation: 20 to SC and 21 to AC (13=PV, 8=AP). There was no difference in LoS in the first 30 days following treatment intervention: AC (median=6 days, IQR 14.5) and SC (median=6 days, IQR 13.3). In patients treated with PV there was a high rate of early treatment failure (6/13; 46%), compared to patients receiving SC (3/20; 15%) (p=0.11) Patients treated with AP had no (0/8 0%) early treatment failures and a median LoS of 1.5 days (IQR 23.8).

Conclusion: There was no difference in LoS between ambulatory and standard care. Pleural Vents had high rates of treatment failure and should not be used in SSP. Atrium Pneumostats are a safer alternative, with a trend towards lower LOS.
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http://dx.doi.org/10.1183/13993003.03375-2020DOI Listing
December 2020

English version of the self-administered Fabry Pain Questionnaire for adult patients.

Orphanet J Rare Dis 2020 10 20;15(1):296. Epub 2020 Oct 20.

Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.

Background: Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Würzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ).

Methods: After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements.

Results: Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items.

Conclusions: We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD.
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http://dx.doi.org/10.1186/s13023-020-01580-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576746PMC
October 2020

Ultrahigh-Temperature Ceramic-Polymer-Derived SiOC Ceramic Composites for High-Performance Electromagnetic Interference Shielding.

ACS Appl Mater Interfaces 2020 Oct 6;12(41):46254-46266. Epub 2020 Oct 6.

Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States.

High-performance electromagnetic interference (EMI) shielding materials for a high-temperature harsh environment are highly required for electronics and aerospace applications. Here, a composite made of ultrahigh-temperature ceramic- and polymer-derived SiOC ceramic (PDC-SiOC) with high EMI shielding was reported for such applications. A total EMI shielding efficiency (SE) of 26.67 dB with a thickness of 0.6 mm at the Ka-band (26.5-40 GHz) was reported for ZrB fabricated by spark plasma sintering, which showed reflection-dominant shielding. A unique interface of t-ZrO was formed after the introduction of PDC-SiOC into ZrB. This interface has better electrical conductivity than SiOC. The composites also displayed reflection-dominant shielding. Accordingly, the composite with a normalized ZrB fraction of 50% pyrolyzed at 1000 °C exhibited a significant SE of 72 dB (over 99.99999% shielded) with a thickness of 3 mm at the entire Ka-band. A maximum SE of 90.8 dB (over 99.9999999% shielded) was achieved with a thickness of 3 mm at around 39.7 GHz.
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http://dx.doi.org/10.1021/acsami.0c08479DOI Listing
October 2020

Cardiac involvement in inflammatory myopathies and inherited muscle diseases.

Curr Opin Rheumatol 2020 11;32(6):528-533

Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose Of Review: To examine recent developments relating to cardiac involvement in the adult idiopathic inflammatory myopathies (IIM) and those inherited muscle diseases which may present in adulthood and mimic IIM.

Recent Findings: Cardiac involvement is a common feature of IIM and inherited muscle diseases. Frequency according to disease subtype varies, with serotype having particular influence in IIM, and genotype in the inherited muscle diseases. Innovative techniques for examining cardiac function have been investigated further, including speckle-tracking echocardiography and cardiac magnetic resonance tomography. The present work has highlighted a likely underestimate of the burden of cardiac disease to date. The complex relationship between IIM, atherosclerosis, and traditional cardiovascular risk factors has been further elucidated. Consensus recommendations for managing patients with inherited muscle diseases and prominent cardiac involvement have been recently published. In addition to supportive care, disease modifying treatments are increasingly becoming available for inherited muscle diseases which may also improve cardiac outcomes.

Summary: Cardiac involvement is associated with significant morbidity and mortality. We suggest having a low threshold for considering the possibility of cardiac involvement in all patients with muscle disease.
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http://dx.doi.org/10.1097/BOR.0000000000000753DOI Listing
November 2020

Development of a Synthetic Population Model for Assessing Excess Risk for Cardiovascular Disease Death.

JAMA Netw Open 2020 09 1;3(9):e2015047. Epub 2020 Sep 1.

Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.

Importance: Evaluating the association of social determinants of health with chronic diseases at the population level requires access to individual-level factors associated with disease, which are rarely available for large populations. Synthetic populations are a possible alternative for this purpose.

Objective: To construct and validate a synthetic population that statistically mimics the characteristics and spatial disease distribution of a real population, using real and synthetic data.

Design, Setting, And Participants: This population-based decision analytical model used data for Allegheny County, Pennsylvania, collected from January 2015 to December 2016, to build a semisynthetic population based on the synthetic population used by the modeling and simulation platform FRED (A Framework for Reconstructing Epidemiological Dynamics). Disease status was assigned to this population using health insurer claims data from the 3 major insurance providers in the county or from the National Health and Nutrition Examination Survey. Biological, social, and other variables were also obtained from the National Health Interview Survey, Allegheny County, and public databases. Data analysis was performed from November 2016 to February 2020.

Exposures: Risk of cardiovascular disease (CVD) death.

Main Outcomes And Measures: Difference between expected and observed CVD death risk. A validated risk equation was used to estimate CVD death risk.

Results: The synthetic population comprised 1 188 112 individuals with demographic characteristics similar to those of the 2010 census population in the same county. In the synthetic population, the mean (SD) age was 40.6 (23.3) years, and 622 997 were female individuals (52.4%). Mean (SD) observed 4-year rate of excess CVD death risk at the census tract level was -40 (523) per 100 000 persons. The correlation of social determinant data with difference between expected and observed CVD death risk indicated that income- and education-based social determinants were associated with risk. Estimating improved social determinants of health and biological factors associated with disease did not entirely remove the excess in CVD death rates. That is, a 20% improvement in the most significant determinants still resulted in 105 census tracts with excess CVD death risk, which represented 24% of the county population.

Conclusions And Relevance: The results of this study suggest that creating a geographically explicit synthetic population from real and synthetic data is feasible and that synthetic populations are useful for modeling disease in large populations and for estimating the outcome of interventions.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.15047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489828PMC
September 2020

Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review.

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

School of Pharmacy, Liverpool John Moore University, Byrom Street, Liverpool L3 3AF, UK.

Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders. Once impaired, dysfunctional mitochondria may impact upon the function of the lysosome by the generation of reactive oxygen species as well as depriving the lysosome of ATP which is required by the V-ATPase proton pump to maintain the acidity of the lumen. Given the reported evidence of mitochondrial dysfunction in LSDs together with the important symbiotic relationship between these two organelles, therapeutic strategies targeting both lysosome and mitochondrial dysfunction may be an important consideration in the treatment of LSDs. In this review we examine the putative mechanisms that may be responsible for mitochondrial dysfunction in reported LSDs which will be supplemented with morphological and clinical information.
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http://dx.doi.org/10.3390/jcm9082596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463786PMC
August 2020

Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers.

Am J Transplant 2021 01 15;21(1):186-197. Epub 2020 Jul 15.

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Subclinical rejection (SCR) screening in kidney transplantation (KT) using protocol biopsies and noninvasive biomarkers has not been evaluated from an economic perspective. We assessed cost-effectiveness from the health sector perspective of SCR screening in the first year after KT using a Markov model that compared no screening with screening using protocol biopsy or biomarker at 3 months, 12 months, 3 and 12 months, or 3, 6, and 12 months. We used 12% subclinical cellular rejection and 3% subclinical antibody-mediated rejection (SC-ABMR) for the base-case cohort. Results favored 1-time screening at peak SCR incidence rather than repeated screening. Screening 2 or 3 times was favored only with age <35 years and with high SC-ABMR incidence. Compared to biomarkers, protocol biopsy yielded more quality-adjusted life years (QALYs) at lower cost. A 12-month biopsy cost $13 318/QALY for the base-case cohort. Screening for cellular rejection in the absence of SC-ABMR was less cost effective with 12-month biopsy costing $46 370/QALY. Screening was less cost effective in patients >60 years. Using biomarker twice or thrice was cost effective only if biomarker cost was <$700. In conclusion, in KT, screening for SCR more than once during the first year is not economically reasonable. Screening with protocol biopsy was favored over biomarkers.
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http://dx.doi.org/10.1111/ajt.16150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744316PMC
January 2021

Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start.

J Neurol 2020 Oct 10;267(10):3038-3053. Epub 2020 Jun 10.

Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, and the André Cournand Pulmonary Physiology Laboratory, Bellevue Hospital, New York, NY, USA.

Objective: To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation.

Methods: Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models.

Results: Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3-126.0). FVC remained stable during the 5-year follow-up (slope = - 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years.

Conclusion: FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.
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http://dx.doi.org/10.1007/s00415-020-09936-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501128PMC
October 2020

British Thoracic Society Training Standards for Thoracic Ultrasound (TUS).

BMJ Open Respir Res 2020 05;7(1)

Respiratory Medicine, Royal Berkshire Hospital, Reading, Reading, UK

Introduction: The British Thoracic Society (BTS) responded to a call from the pleural community to establish this new Training Standard to detail the capabilities in practice for thoracic ultrasound (TUS), which will build on the previous curricula and extend the remit to include training for the emergency provision of TUS.

Methods: BTS convened a working group to produce a set of Training Standards.

Results: This document provides a comprehensive Training Standard for TUS facilitating timely and improved management of patients with respiratory presentations, particularly (but not exclusively) pleural pathologies.

Discussion: The Training Standards document will be widely disseminated.
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http://dx.doi.org/10.1136/bmjresp-2019-000552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245450PMC
May 2020

Manometry performed at indwelling pleural catheter insertion to predict unexpandable lung.

J Thorac Dis 2020 Apr;12(4):1374-1384

Academic Respiratory Unit, University of Bristol, Bristol, UK.

Background: The finding of unexpandable lung (UL) at an early timepoint is of increasing importance in guiding treatment decisions in patients with malignant pleural effusion (MPE). Pleural manometry is the most common technique to delineate UL, however it has never been measured via an indwelling pleural catheter (IPC). To further the evidence base we analysed all patients in the IPC-PLUS study who had manometry performed during IPC insertion for the ability to predict substantial UL using manometry.

Methods: All patients enrolled in IPC-PLUS who had manometry performed at IPC insertion and radiographic assessment of UL at day 10 were included. Elastance curves were visually inspected for each patient. Initial pleural pressure, closing pleural pressure, and terminal elastance were analysed for their differences and predictive ability in those with substantial UL, defined as ≥25% entrapment on chest radiography.

Results: A total of 89 patients had manometry performed at IPC insertion with subsequent radiographic assessment of UL and interpretable elastance curves. Those with substantial UL had a significantly lower median closing pleural pressure (-15.00 0.00 cmHO, P=0.012) and higher terminal elastance (12.03 8.59 cmHO/L, P=0.021) compared to a combined group with no or partial UL. However, the predictive ability of these factors to discriminate substantial UL was poor, with areas under the receiver operating characteristic curves of 0.695 and 0.680 for closing pleural pressure and elastance respectively.

Conclusions: Our results suggest that manometry is not useful in accurately predicting substantial UL when used via an IPC at the time of insertion.
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http://dx.doi.org/10.21037/jtd.2020.02.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212160PMC
April 2020

Method for economic evaluation of bacterial whole genome sequencing surveillance compared to standard of care in detecting hospital outbreaks.

Clin Infect Dis 2020 May 5. Epub 2020 May 5.

Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Whole genome sequencing (WGS) surveillance and electronic health record data mining have the potential to greatly enhance the identification and control of hospital outbreaks. The objective was to develop methods for examining economic value of a WGS surveillance-based infection prevention (IP) program compared to Standard of Care (SoC).

Methods: The economic value of a WGS surveillance-based IP program was assessed from a hospital's perspective using historical outbreaks from 2011-2016. We used transmission network of outbreaks to estimate incremental cost per transmission averted. The number of transmissions averted depended on the effectiveness of intervening against transmission routes, time from transmission to positive culture results and time taken to obtain WGS results and intervene on the transmission route identified. The total cost of an IP program included cost of staffing, WGS, and treating infections.

Results: Approximately 41 out of 89 (46%) transmissions could have been averted under the WGS surveillance-based IP program and it was found to be a less costly and more effective strategy than SoC. The results were most sensitive to the cost of performing WGS and the number of isolates sequenced per year under WGS surveillance. The probability of the WGS surveillance-based IP program being cost-effective was 80% if willingness to pay exceeded $2,400 per transmission averted.

Conclusions: The proposed economic analysis is a useful tool to examine economic value of a WGS surveillance-based IP program. These methods will be applied to a prospective evaluation of WGS surveillance compared to SoC.
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http://dx.doi.org/10.1093/cid/ciaa512DOI Listing
May 2020

Age and generational patterns of overdose death risk from opioids and other drugs.

Nat Med 2020 05 4;26(5):699-704. Epub 2020 May 4.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures.
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http://dx.doi.org/10.1038/s41591-020-0855-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086189PMC
May 2020

Influence of Anesthesia and Clinical Variables on the Firing Rate, Coefficient of Variation and Multi-Unit Activity of the Subthalamic Nucleus in Patients with Parkinson's Disease.

J Clin Med 2020 Apr 24;9(4). Epub 2020 Apr 24.

School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Background: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery.

Methods: Data from 78 patients with Parkinson's disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups.

Results: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables.

Conclusion: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.
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http://dx.doi.org/10.3390/jcm9041229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230272PMC
April 2020

Criteria and Process for Initiating and Developing an ISPOR Good Practices Task Force Report.

Value Health 2020 Apr;23(4):409-415

Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

The International Society for Pharmacoeconomics and Outcomes Research (ISPOR)'s "Good Practices Task Force" reports are highly cited, multistakeholder perspective expert guidance reports that reflect international standards for health economics and outcomes research (HEOR) and their use in healthcare decision making. In this report, we discuss the criteria, development, and evaluation/consensus review and approval process for initiating a task force. The rationale for a task force must include a justification, including why this good practice guidance is important and its potential impact on the scientific community. The criteria include: (1) necessity (why is this task force required?); (2) a methodology-oriented focus (focus on research methods, approaches, analysis, interpretation, and dissemination); (3) relevance (to ISPOR's mission and its members); (4) durability over time; (5) broad applicability; and 6) an evidence-based approach. In addition, the proposal must be a priority specifically for ISPOR. These reports are valuable to researchers, academics, students, health technology assessors, medical technology developers and service providers, those working in other commercial entities, regulators, and payers. These stakeholder perspectives are represented in task force membership to ensure the report's overall usefulness and relevance to the global ISPOR membership. We hope that this discussion will bring transparency to the process of initiating, approving, and producing these task force reports and encourage participation from a diverse range of experts within and outside ISPOR.
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http://dx.doi.org/10.1016/j.jval.2020.03.001DOI Listing
April 2020

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

J Inherit Metab Dis 2020 09 16;43(5):1002-1013. Epub 2020 Apr 16.

Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.
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http://dx.doi.org/10.1002/jimd.12234DOI Listing
September 2020

Novel Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency.

Front Genet 2020 25;11:24. Epub 2020 Feb 25.

Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.

Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely frameshift variant in (m.14512_14513del) and a novel maternally-inherited transversion mutation in were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the variant was undetectable while the mutant heteroplasmy level of the variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.
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http://dx.doi.org/10.3389/fgene.2020.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052259PMC
February 2020

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brain 2020 02;143(2):452-466

Department of Neurology, Donders Centre for Medical Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
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http://dx.doi.org/10.1093/brain/awz410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009512PMC
February 2020

White matter structure and myelin-related gene expression alterations with experience in adult rats.

Prog Neurobiol 2020 04 27;187:101770. Epub 2020 Jan 27.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

White matter (WM) plasticity during adulthood is a recently described phenomenon by which experience can shape brain structure. It has been observed in humans using diffusion tensor imaging (DTI) and myelination has been suggested as a possible mechanism. Here, we set out to identify molecular and cellular changes associated with WM plasticity measured by DTI. We combined DTI, immunohistochemistry and mRNA expression analysis and examined the effects of somatosensory experience in adult rats. First, we observed experience-induced DTI differences in WM and in grey matter structure. C-Fos mRNA expression, a marker of cortical activity, in the barrel cortex correlated with the MRI WM metrics, indicating that molecular correlates of cortical activity relate to macroscale measures of WM structure. Analysis of myelin-related genes revealed higher myelin basic protein (MBP) mRNA expression. Higher MBP protein expression was also found via immunohistochemistry in WM. Finally, unbiased RNA sequencing analysis identified 134 differentially expressed genes encoding proteins involved in functions related to cell proliferation and differentiation, regulation of myelination and neuronal activity modulation. In conclusion, macroscale measures of WM plasticity are supported by both molecular and cellular evidence and confirm that myelination is one of the underlying mechanisms.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086231PMC
April 2020

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

JAMA 2020 Jan;323(1):60-69

Oxford Respiratory Trials Unit, Nuffield Department of Experimental Medicine, University of Oxford, United Kingdom.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations.

Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis.

Design, Setting, And Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung.

Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry.

Main Outcomes And Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days.

Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes.

Conclusions And Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences.

Trial Registration: ISRCTN Identifier: ISRCTN47845793.
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http://dx.doi.org/10.1001/jama.2019.19997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990658PMC
January 2020