Publications by authors named "Edward Smith"

461 Publications

Surface Topography Effects on Pool Boiling via Non-equilibrium Molecular Dynamics Simulations.

Langmuir 2021 Apr 29. Epub 2021 Apr 29.

Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.

In this work, we investigate nucleate pool boiling via non-equilibrium molecular dynamics simulations. The effect of nano-structured surface topography on nucleation and transition to a film-like boiling regime is studied at the molecular scale, by varying the cavity aspect ratio, wall superheat, and wettability through a systematic parametric analysis conducted on a Lennard-Jones (LJ) system. The interplay of the aforementioned factors is rationalized by means of a classical nucleation theory-based model. The solid surface is heated uniformly from the bottom in order to induce the nanobubble nucleation. Insight into the cavity behavior in heat transfer problems is achieved by looking at temperature and heat flux profiles inside the cavity itself, as well as at the time of nucleation, for different operating conditions. The role of the cavity size in controlling the vapor embryo formation is highlighted, and its dependence on the other investigated parameters is summarized in a phase diagram. Our results show that heterogeneity at the nanoscale plays a key role in determining pool boiling heat transfer performance, suggesting a promising approach to optimize nanostructured surfaces for energy and thermal management applications.
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http://dx.doi.org/10.1021/acs.langmuir.1c00779DOI Listing
April 2021

Non-invasive Urinary Biomarkers in Moyamoya Disease.

Front Neurol 2021 1;12:661952. Epub 2021 Apr 1.

Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.

A major difficulty in treating moyamoya disease is the lack of effective methods to detect novel or progressive disease prior to the onset of disabling stroke. More importantly, a tool to better stratify operative candidates and quantify response to therapy could substantively complement existing methods. Here, we present proof-of-principle data supporting the use of urinary biomarkers as diagnostic adjuncts in pediatric moyamoya patients. Urine and cerebrospinal fluid specimens were collected from pediatric patients with moyamoya disease and a cohort of age and sex-matched control patients. Clinical and radiographic data were paired with measurements of a previously validated panel of angiogenic proteins quantified by ELISA. Results were compared to age and sex-matched controls and subjected to statistical analyses. Evaluation of a specific panel of urinary and cerebrospinal fluid biomarkers by ELISA demonstrated significant elevations of angiogenic proteins in samples from moyamoya patients compared to matched controls. ROC curves for individual urinary biomarkers, including MMP-2, MMP-9, MMP-9/NGAL, and VEGF, showed excellent discrimination. The optimal urinary biomarker was MMP-2, providing a sensitivity of 88%, specificity of 100%, and overall accuracy of 91%. Biomarker levels changed in response to therapy and correlated with radiographic evidence of revascularization. We report, for the first time, identification of a panel of urinary biomarkers that predicts the presence of moyamoya disease. These biomarkers correlate with presence of disease and can be tracked from the central nervous system to urine. These data support the hypothesis that urinary proteins are useful predictors of the presence of moyamoya disease and may provide a basis for a novel, non-invasive method to identify new disease and monitor known patients following treatment.
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http://dx.doi.org/10.3389/fneur.2021.661952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047329PMC
April 2021

Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.

Acta Neuropathol Commun 2021 04 14;9(1):70. Epub 2021 Apr 14.

Institute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, UK.

Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.
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http://dx.doi.org/10.1186/s40478-021-01172-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048291PMC
April 2021

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis-Why and How?

Front Physiol 2021 17;12:645857. Epub 2021 Mar 17.

Department of Nephrology, The Royal Melbourne Hospital (RMH), Melbourne, VIC, Australia.

Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.
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http://dx.doi.org/10.3389/fphys.2021.645857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010236PMC
March 2021

Monogamy in a Moment: How do Brief Social Interactions Change Over Time in Pair-Bonded Zebra Finches ()?

Integr Org Biol 2020 26;2(1):obaa034. Epub 2020 Dec 26.

Department of Psychology, University of Maryland, College Park, MD, USA.

Research on monogamy has largely focused on marked behaviors that are unique to pair bonded partners. However, these marked behaviors represent only a subset of the pair-directed behaviors that partners engage in; the influence of pair bonding on mundane or subtle social interactions among partners remains largely unknown. In this study, we describe the changes that occur during brief social reunions (or greets) over the course of pair bonding in zebra finches. We quantified pair-directed behavior during 5-min reunions from three stages of pair bonding: initial pairing (between 4 and 72 h), early pairing (1-2 weeks), and late pairing (>1 month). These social interactions were operationalized in multiple ways. First, we quantified the overall activity levels (call and movement rates) for both the male and female. Overall, females were more active than males, but for both males and females calling activity was highest at initial pairing. We quantified behavioral coordination between partners in two ways: (1) similarity in call and movement rates between partners and (2) temporal synchrony of calls and movements between partners (via sliding correlation coefficients of time-stamped calls and movements). Overall, there were no effects of pairing stage on behavioral coordination. Finally, we used principal component analyses to disentangle behavioral coordination from the activity levels of the male and female. These results contribute to a growing line of evidence that male and female zebra finches differentially contribute to social dynamics and highlight the influence of pair bonding on the development of social dynamics. Furthermore, our preliminary analyses raise the hypothesis that behavioral coordination during the earliest phases of pairing is modulated by the extent and nature of prior experience. Overall, while behavioral coordination is clearly important for many salient interactions such as duetting, courtship displays, and biparental care, the significance of mundane social interactions for monogamous partnerships remains largely unknown.
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http://dx.doi.org/10.1093/iob/obaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810576PMC
December 2020

Effect of a medium cut-off dialyzer on protein-bound uremic toxins and mineral metabolism markers in patients on hemodialysis.

Hemodial Int 2021 Mar 28. Epub 2021 Mar 28.

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.

Introduction: Hemodialysis (HD) with medium cut-off (MCO) dialyzers may expand molecular clearance, predominantly larger middle molecules (molecular weight 25-60 kDa). However, the impact of MCO dialyzers on long-term clearance of various other components of the uremic milieu is unknown. The tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) provided an opportunity to assess the effect of MCO dialyzers on protein-bound uremic toxins and novel markers of mineral metabolism.

Methods: This exploratory sub-study of REMOVAL-HD evaluated changes in protein-bound solutes (total and free indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) and mineral metabolism markers (intact fibroblast growth factor-23 [iFGF23], fetuin-A and endogenous calciprotein particles [CPP-1 and CPP-2]). Mid-week, pre-HD serum samples were collected at baseline and after 12 and 24 weeks of MCO use in stable adult patients. Change from baseline to Week 12 and 24 was estimated using linear mixed effects models.

Findings: Eighty-nine participants were studied (mean age 67 ± 15 years, 38% female, 51% diabetic, median urine output 200 ml/24 h). Serum iFGF23 was reduced at Week 12 compared to baseline (-26.8% [95%CI -39.7, -11.1], p = 0.001), which was sustained at Week 24 (-21.7% [95%CI -35.7, -4.5], p = 0.012). There was no significant change in serum IS, PCS, fetuin-A, CPP-1, or CPP-2.

Discussion: The use of a MCO dialyzer over 24 weeks was associated with a sustained reduction in FGF23, while other measured components of the uremic milieu were not significantly altered. Further studies are required to determine whether FGF23 reduction is associated with improved patient outcomes.
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http://dx.doi.org/10.1111/hdi.12924DOI Listing
March 2021

Patients' and caregivers' maximum acceptable risk of death for non-curative gene therapy to treat Duchenne muscular dystrophy.

Mol Genet Genomic Med 2021 Mar 23:e1664. Epub 2021 Mar 23.

RTI Health Solutions, Research Triangle Park, NC, USA.

Background: Gene therapy offers an etiologically targeted treatment for genetic disorders. Little is known about the acceptance of mortality risk among patients with progressive, fatal conditions. We assessed patients' and caregivers' maximum acceptable risk (MAR) of mortality for gene therapy when used to treat Duchenne muscular dystrophy (DMD).

Methods: The threshold technique was used to assess tolerance for mortality risks using a hypothetical vignette. Gene therapy was described as non-curative and resulting in a slowing of progression and with a 10-year benefit duration. MAR was analyzed using interval regression for gene therapy initiated "now"; in the last year of walking well; in the last year of being able to bring arms to mouth; and in newborns (for caregivers only).

Results: Two hundred eighty-five caregivers and 35 patients reported the greatest MAR for gene therapy initiated in last year of being able to lift arms (mean MAR 6.3%), followed by last year of walking well (mean MAR 4.4%), when used "now" (mean MAR 3.5%), and when used in the newborn period (mean MAR 2.1%, caregivers only). About 35% would accept ≥200/2000 risk in the last year of being able to lift arms. Non-ambulatory status predicted accepting 1.8 additional points in MAR "now" compared with ambulatory status (p = 0.010). Respondent type (caregiver or patient) did not predict MAR.

Conclusion: In this first quantitative study to assess MAR associated with first-generation DMD gene therapy, we find relatively high tolerance for mortality risk in response to a non-curative treatment scenario. Risk tolerance increased with disease progression. Patients and caregivers did not have significantly different MAR. These results have implications for protocol development and shared decision making.
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http://dx.doi.org/10.1002/mgg3.1664DOI Listing
March 2021

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.

Lancet Neurol 2021 04 17;20(4):284-293. Epub 2021 Mar 17.

Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA; Department of Neurology, Ohio State University, Columbus, OH, USA.

Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.

Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).

Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).

Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.

Funding: Novartis Gene Therapies.
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http://dx.doi.org/10.1016/S1474-4422(21)00001-6DOI Listing
April 2021

Current trends in pediatric moyamoya: a survey of international practitioners.

Childs Nerv Syst 2021 Mar 10. Epub 2021 Mar 10.

Pediatric Neurosurgery Department, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.

Objective: Moyamoya angiopathy (MM) is a chronic, progressive steno-occlusive arteriopathy of the distal internal carotid artery and its proximal branches. MM is recognized as a shared end-pathway common to a broad range of inciting pathologies, suggesting that tailored management is important. Pediatric MM differs from MM in adults. Currently, there are many uncertainties and controversies regarding the diagnosis and management of children with MM. Hence, we conducted an international survey to identify the contemporary management trends followed worldwide.

Methods: A survey relating to lifestyle modifications, medical management, diagnosis, surgical management, and follow-up for pediatric MM was circulated across web-based platforms, through various international pediatric neurological and neurosurgical societies. Data collected included geographic region of practice, experience, responses to questions, and comments.

Results: One hundred twenty-seven responses were evaluated (104 neurosurgeons and 23 neurologists, from 32 countries, across 6 continents). We found wide variations in the recommendations for management and lifestyle modification, with significant differences between regions of practice. Eighty percent recommend restrictions on physical activity, particularly for symptomatic and non-operated patients. Eighty-four percent prescribe aspirin. Sixty-five percent perform indirect revascularization. Seventy-eight percent recommend performing a staged surgery for bilateral MM. Only 26% perform acetazolamide challenge SPECT to evaluate brain perfusion. Only 15% of responders were from highly experienced centers.

Conclusion: This survey reflects the contemporary trends in management of pediatric MM, while highlighting the heterogeneity in the management approach of these patients. There is a need for multicenter, international studies to evaluate the safety, efficacy, and long-term outcome of various aspects of treatment of these patients.
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http://dx.doi.org/10.1007/s00381-021-05074-2DOI Listing
March 2021

HBEGF: an EGF-like growth factor with FGF23-like activity?

Kidney Int 2021 03;99(3):539-542

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia; Department of Medicine, University of Melbourne, Parkville, Australia.

Renal signaling networks downstream of FGF23 are not well delineated, but elucidating them may offer an opportunity to control target genes independent of FGF23 in states of dysregulated mineral metabolism. Ni et al. identify HBEGF as a paracrine/autocrine factor in the proximal tubules of mice that mimics the inductive effect of FGF23 on the vitamin D-catabolizing enzyme 24-hydroxylase through a common mitogen-activated protein kinase-dependent pathway. An understanding of how these findings relate to human disease is eagerly anticipated.
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http://dx.doi.org/10.1016/j.kint.2020.11.011DOI Listing
March 2021

Neogenin is highly expressed in diffuse intrinsic pontine glioma and influences tumor invasion.

Brain Res 2021 Jul 9;1762:147348. Epub 2021 Feb 9.

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, 02115 Boston, MA, USA; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, 02115 Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brainres.2021.147348DOI Listing
July 2021

A high-quality genome assembly and annotation of the gray mangrove, Avicennia marina.

G3 (Bethesda) 2021 Jan;11(1)

Center for Genomics and Systems Biology, New York University - Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates.

The gray mangrove [Avicennia marina (Forsk.) Vierh.] is the most widely distributed mangrove species, ranging throughout the Indo-West Pacific. It presents remarkable levels of geographic variation both in phenotypic traits and habitat, often occupying extreme environments at the edges of its distribution. However, subspecific evolutionary relationships and adaptive mechanisms remain understudied, especially across populations of the West Indian Ocean. High-quality genomic resources accounting for such variability are also sparse. Here we report the first chromosome-level assembly of the genome of A. marina. We used a previously release draft assembly and proximity ligation libraries Chicago and Dovetail HiC for scaffolding, producing a 456,526,188-bp long genome. The largest 32 scaffolds (22.4-10.5 Mb) accounted for 98% of the genome assembly, with the remaining 2% distributed among much shorter 3,759 scaffolds (62.4-1 kb). We annotated 45,032 protein-coding genes using tissue-specific RNA-seq data in combination with de novo gene prediction, from which 34,442 were associated to GO terms. Genome assembly and annotated set of genes yield a 96.7% and 95.1% completeness score, respectively, when compared with the eudicots BUSCO dataset. Furthermore, an FST survey based on resequencing data successfully identified a set of candidate genes potentially involved in local adaptation and revealed patterns of adaptive variability correlating with a temperature gradient in Arabian mangrove populations. Our A. marina genomic assembly provides a highly valuable resource for genome evolution analysis, as well as for identifying functional genes involved in adaptive processes and speciation.
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http://dx.doi.org/10.1093/g3journal/jkaa025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022769PMC
January 2021

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

Arterioscler Thromb Vasc Biol 2021 Apr 4;41(4):1446-1458. Epub 2021 Feb 4.

Department of Medicine, Centre for Cardiometabolic and Vascular Science, University College London, United Kingdom (L.C., K.E.W., E.C., I.P.-T.).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610443PMC
April 2021

Profiles of Adolescent Leisure Motivation and Substance Use in the HealthWise South Africa Research Trial: A Person-Centered Approach.

Leis Sci 2020 10;42(5-6):482-501. Epub 2018 Nov 10.

Prevention Research Center, The Pennsylvania State University, University Park, PA and Faculty of Health Sciences, University of the Western Cape, South Africa.

Engaging in intrinsically motivated behaviors, both within and outside of the leisure context, is associated with well-being. However, individuals can be driven by multiple types of motivation simultaneously, and the impact of constellations of leisure motivation is relatively unknown. The current study uses South African adolescents in the HealthWise South Africa efficacy trial (=2,204; =14.0) to identify profiles of leisure motivation, examine the association between profiles and substance use, and evaluate the impact of HealthWise on changes in motivation profiles over time. Results indicate three distinct profiles: high consistent motivation, low consistent motivation, and high intrinsic motivation. Members of the high intrinsic profile had the lowest odds of substance use. Profiles were fairly stable across all time points except for females in a high-training intervention school. Results illustrate the importance of identifying and understanding typologies of leisure motivation and health across time, which can be used to promote positive development in adolescents.
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http://dx.doi.org/10.1080/01490400.2018.1499055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821964PMC
November 2018

Scoliosis with Chiari I malformation without associated syringomyelia.

Spine Deform 2021 Jan 20. Epub 2021 Jan 20.

Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA.

Purpose: Many patients with presumed idiopathic scoliosis are found to have Chiari I malformation (CM-I) on MRI. The objective of this study is to report on scoliosis progression in CM-I with no syringomyelia.

Methods: A retrospective review of patients with scoliosis and CM-I was conducted from 1997 to 2015. Patients with syringomyelia and/or non-idiopathic scoliosis were excluded. Clinical and radiographic characteristics were recorded at presentation and latest follow-up. CM-I was defined as the cerebellar tonsil extending 5 mm or more below the foramen magnum on MRI.

Results: Thirty-two patients (72% female) with a mean age of 11 years (range 1-16) at scoliosis diagnosis were included. The average initial curve was 30.3° ± SD 16.3. The mean initial Chiari size was 9.6 mm SD ± 4.0. Fifteen (46.9%) experienced Chiari-related symptoms, and three (9%) patients underwent Posterior Fossa Decompression (PFD) to treat these symptoms. 10 (31%) patients went on to fusion, progressing on average 13.6° (95% CI 1.6-25.6°). No association was detected between decompression and either curve progression or fusion (p = 0.46, 0.60). For those who did not undergo fusion, curve magnitude progressed on average 1.0° (95% CI - 4.0 to 5.9°). There was no association between age, Chiari size, presence of symptoms, initial curve shape, or bracing treatment and fusion.

Conclusion: Patients with CM-I and scoliosis may not require surgical treatment, including PFD and fusion. Scoliosis curvature stabilized in the non-surgical population at an average progression of 1.0°. These results suggest that CM-I with no syringomyelia has minimal effect on scoliosis progression.
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http://dx.doi.org/10.1007/s43390-021-00286-7DOI Listing
January 2021

Supporting South African High School Teachers' Implementation of a Prevention Program via Abridged Consultation: Outcomes and Moderators.

Am J Community Psychol 2020 Dec 16. Epub 2020 Dec 16.

University of the Western Cape, Bellville, South Africa.

Research is lacking on consultation support for school-based evidence-based programs (EBP) intended to prevent youths' risky behaviors in schools in low-resourced settings like high schools surrounding Cape Town, South Africa. Thus, this study's objective was to examine implementation outcomes and moderators of an abridged consultation condition for supporting teachers in better implementing HealthWise, an EBP for preventing youth risky sexual and substance use behaviors. Twenty-one schools with 33 teachers receiving abridged consultation (i.e., three consultation meetings, text message reminders, lesson plans, and support kits) were compared to 26 schools with 41 teachers that did not receive any consultation. Teachers with abridged consultation self-reported delivering more HealthWise content. Moderation analyses found teachers with lower educational degrees, who received abridged consultation reported more student interest in HealthWise. When there was higher school-level risk, teachers who received abridged consultation marginally self-reported adapting HealthWise more. Findings suggest consultation support that is abridged or a lower dose than is typical can be feasible in such a low-resourced, overburdened setting while still being associated with EBP coverage, student interest, and adaptation. However, moderation findings suggest contextual factors should be considered to match teachers/schools to the implementation support that best suits them.
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http://dx.doi.org/10.1002/ajcp.12494DOI Listing
December 2020

Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy.

J Pers Med 2020 Nov 19;10(4). Epub 2020 Nov 19.

Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA.

The development of therapeutics for muscle diseases such as facioscapulohumeral dystrophy (FSHD) is impeded by a lack of objective, minimally invasive biomarkers. Here we identify circulating miRNAs and proteins that are dysregulated in early-onset FSHD patients to develop blood-based molecular biomarkers. Plasma samples from clinically characterized individuals with early-onset FSHD provide a discovery group and are compared to healthy control volunteers. Low-density quantitative polymerase chain reaction (PCR)-based arrays identify 19 candidate miRNAs, while mass spectrometry proteomic analysis identifies 13 candidate proteins. Bioinformatic analysis of chromatin immunoprecipitation (ChIP)-seq data shows that the FSHD-dysregulated DUX4 transcription factor binds to regulatory regions of several candidate miRNAs. This panel of miRNAs also shows ChIP signatures consistent with regulation by additional transcription factors which are up-regulated in FSHD (FOS, EGR1, MYC, and YY1). Validation studies in a separate group of patients with FSHD show consistent up-regulation of miR-100, miR-103, miR-146b, miR-29b, miR-34a, miR-454, miR-505, and miR-576. An increase in the expression of S100A8 protein, an inflammatory regulatory factor and subunit of calprotectin, is validated by Enzyme-Linked Immunosorbent Assay (ELISA). Bioinformatic analyses of proteomics and miRNA data further support a model of calprotectin and toll-like receptor 4 (TLR4) pathway dysregulation in FSHD. Moving forward, this panel of miRNAs, along with S100A8 and calprotectin, merit further investigation as monitoring and pharmacodynamic biomarkers for FSHD.
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http://dx.doi.org/10.3390/jpm10040236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711540PMC
November 2020

Quantifying the Deposition of Airborne Particulate Matter Pollution on Skin Using Elemental Markers.

Environ Sci Technol 2020 12 19;54(24):15958-15967. Epub 2020 Nov 19.

State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing, 100084, China.

Airborne particulate matter (PM) pollution is an environmental and health concern. The health impact of PM pollution has typically focused on the respiratory system. The impact of PM pollution on skin has been largely understudied due to the lack of a quantitative method to measure the deposition on skin. This manuscript presents a method to quantify PM pollution on skin using elemental markers as a proxy for PM. Skin tape strips were collected from forehead and buttock of 100 outdoor workers in Beijing, China. Skin samples were analyzed for 19 elemental markers using inductively coupled plasma mass spectrometry. To determine the specific elemental signature of PM for the region, air samples were collected over 7 days for PM < 2.5 μm (PM) and analyzed for the same 19 elements as the skin samples. An enrichment factor was calculated for each element and the potential source was evaluated. Using the elemental markers unique to PM pollution for the region, the PM concentration deposited on skin was determined to be 0.621-2.53 μg PM /cm. This method can be re-applied in different regions and the PM concentration on skin can inform future studies on the health impact of air pollution on skin.
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http://dx.doi.org/10.1021/acs.est.0c03901DOI Listing
December 2020

Cerebrovascular Disease Progression in Patients With Arg179 Pathogenic Variants.

Neurology 2021 01 16;96(4):e538-e552. Epub 2020 Nov 16.

From the Departments of Neurology (A.L., S.L.S., P.L.M.) and Radiology (J.B.P., J.K.-K., P.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Internal Medicine (E.R., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Department of Neuroradiology (A.L., M.C.), Goethe University, Frankfurt am Main, Germany; andDepartment of Neurosurgery (E.S.), Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with Arg179 pathogenic variants.

Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury.

Results: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis.

Conclusions: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905785PMC
January 2021

TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts.

Sci Rep 2020 10 21;10(1):17914. Epub 2020 Oct 21.

Department of Nephrology, The Royal Melbourne Hospital (RMH), Grattan Street, Parkville, VIC, 3050, Australia.

TGF-β1 reprograms metabolism in renal fibroblasts, inducing a switch from oxidative phosphorylation to aerobic glycolysis. However, molecular events underpinning this are unknown. Here we identify that TGF-β1 downregulates acetyl-CoA biosynthesis via regulation of the pyruvate dehydrogenase complex (PDC). Flow cytometry showed that TGF-β1 reduced the PDC subunit PDH-E1α in fibroblasts derived from injured, but not normal kidneys. An increase in expression of PDH kinase 1 (PDK1), and reduction in the phosphatase PDP1, were commensurate with net phosphorylation and inactivation of PDC. Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation. The effect of TGF-β1 on PDC activity, acetyl-CoA, αSMA and pro-collagen I was also ameliorated by sodium dichloroacetate, a small molecule inhibitor of PDK. A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.
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http://dx.doi.org/10.1038/s41598-020-74919-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578649PMC
October 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Hydrodynamics across a fluctuating interface.

J Chem Phys 2020 Oct;153(13):134705

School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.

Understanding what happens inside the rippling and dancing surface of a liquid remains one of the great challenges of fluid dynamics. Using molecular dynamics, we can pick apart the interface structure and understand surface tension. In this work, we derive an exact mechanical formulation of hydrodynamics for a liquid-vapor interface using a control volume, which moves with the surface. This mathematical framework provides the local definition of hydrodynamic fluxes at any point on the surface. These are represented not only by the flux of molecules and intermolecular interactions acting across the surface but also as a result of the instantaneous local curvature and movement of the surface itself. By explicitly including the surface dynamics in the equations of motion, we demonstrate an exact balance between kinetic and configurational pressure normal to the surface. The hydrodynamic analysis makes no assumptions regarding the probability distribution function, so it is valid for any system arbitrarily far from thermodynamic equilibrium. The presented equations provide a theoretical basis for the study of time-evolving interface phenomena, such as bubble nucleation, droplet dynamics, and liquid-vapor instabilities.
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http://dx.doi.org/10.1063/5.0022530DOI Listing
October 2020

Parenting Practice, Leisure Experience, and Substance Use Among South African Adolescents.

J Leis Res 2020 21;51(1):36-55. Epub 2019 Jun 21.

The Pennsylvania State University, University of the Western Cape, South Africa.

There is limited understanding of parents' role in positive youth/adolescent development through leisure in developing countries. Using a sample of 6626 8 grade students in South Africa, this study examined the interrelationships among parenting practice, adolescents' leisure experience, and substance use. Results of structural equation modeling showed that parental leisure involvement was associated with less substance use, while parental leisure over-control was associated with greater substance use. The relationship of parental leisure involvement to substance use was mediated by healthy leisure engagement. The relationship of parental leisure over-control to substance use, on the other hand, was mediated by leisure boredom and healthy leisure engagement. The model path coefficients had little variation between genders and socioeconomic groups except that parental leisure over-control had a stronger positive relationship with leisure boredom for males than females. Theoretical and practical implications were discussed.
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http://dx.doi.org/10.1080/00222216.2019.1620144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518372PMC
June 2019

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

PLoS Med 2020 09 21;17(9):e1003222. Epub 2020 Sep 21.

University of California, Davis, Davis, California, United States of America.

Background: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD.

Methods And Findings: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators.

Conclusions: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy.

Trial Registration: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].
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http://dx.doi.org/10.1371/journal.pmed.1003222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505441PMC
September 2020

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington'S Disease Model.

Brain Commun 2020 3;2(2):fcaa066. Epub 2020 Aug 3.

Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, Queen Square, WC1N 3BG, UK.

Huntington's disease is caused by the expansion of a CAG repeat within exon 1 of the gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington's disease, that were known to abrogate somatic instability in Huntington's disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 with 90 CAGs, a mutation that causes juvenile Huntington's disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington's disease patient's blood, but which has been detected in post-mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG) mice and that this correlated with the onset of transcriptional dysregulation. Whereas in R6/2(CAG) mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG) brains have different properties to those in the R6/2(CAG) mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilized by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG) brains polymerize into larger structures that appear as inclusion bodies. These data emphasize that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.
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http://dx.doi.org/10.1093/braincomms/fcaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425396PMC
August 2020

Clinical status and evolution in moyamoya: which angiographic findings correlate?

Brain Commun 2019 30;1(1):fcz029. Epub 2019 Oct 30.

Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Moyamoya is a progressive steno-occlusive cerebrovascular pathology of unknown aetiology that usually involves the terminal portions of the internal carotid arteries and/or the proximal portions of the anterior and middle cerebral arteries bilaterally. The pre-operative Suzuki staging system and post-operative Matsushima grade are nearly universally used markers of natural history and surgical revascularization results, respectively, but their correlation with clinical and radiographic manifestations of moyamoya has not been systematically evaluated in a large cohort. This study evaluated the strength of correlations between pre- and post-operative angiographic parameters and clinical status among paediatric patients with moyamoya. The participants included 58 patients of mean age 11 years at the time of surgery who underwent bilateral indirect revascularization in the same procedure at Boston Children's Hospital, between January 2010 and December 2015. All included patients had available pre-operative and 1-year post-operative digital subtraction angiography. Clinical data included presenting symptoms, degree of functional incapacity, and peri-operative and long-term complications. Radiographic data included pre-operative Suzuki stage, degree of arterial stenosis, a novel collateral score, the presence of hypovascular territories on digital subtraction angiography, and post-operative Matsushima grade and evolution of stenosis. Chi-squared test and Pearson coefficient were used for correlation studies for categorical variables and Spearman's rho was used for correlation studies for continuous variables. Results showed that Suzuki stage, collateral score and degree of stenosis were insufficient to predict clinical presentation, pre-operative incapacity and radiographic presentation, whereas the presence of hypovascular territories was correlated with all of these. At 1-year follow-up, Matsushima grade was insufficient for predicting peri-operative or long-term complications, nor did it correlate with post-operative incapacity. The presence of hypovascular territories at 1-year follow-up was correlated with the incidence of post-operative ischaemic symptoms.
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http://dx.doi.org/10.1093/braincomms/fcz029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425301PMC
October 2019

Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial.

Kidney Int Rep 2020 Sep 29;5(9):1432-1447. Epub 2020 Jun 29.

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Introduction: Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non-calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate-containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects.

Methods: We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC-treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed.

Results: Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (-70%, 95% confidence interval [CI] -90% to -15%,  = 0.02). In subgroup analysis, this effect was confined to those receiving SC (-83.4%, 95% CI -95.7% to -36.8%,  = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (-2.0 m/s, 95% CI -2.9 to -1.1; -57%, 95% CI -73% to -30%, respectively, both  = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups.

Discussion: Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.
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http://dx.doi.org/10.1016/j.ekir.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486191PMC
September 2020

Single-institution case series of pituitary biopsy for suspected germinoma in the pediatric population: diagnostic utility, operative risks, and biopsy approaches.

Sci Rep 2020 09 17;10(1):15257. Epub 2020 Sep 17.

Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Little has been reported on the safety and efficacy of pituitary biopsy in the pediatric population for suspected germinoma. An updated review is needed. Patients who underwent biopsy (endoscopic endonasal vs. open craniotomy) for isolated pituitary stalk thickening were identified. Age, pre- and post-operative endocrine status, surgical approach, length of surgery, estimated blood loss, surgical morbidity, length of ICU stay, total length of stay, and pathology reports were reviewed. Nine patients met inclusion criteria. Germinoma diagnosis was rendered in 7 of 9 patients; 1 patient required two biopsy attempts. Two-patients had histology consistent with inflammation and a subsequently self-limited disease course. Average operative time, blood loss, ICU stay and overall length of stay was just over 2 h, 28 mL, 1.6 days and 3.7 days respectively. There were no intraoperative complications and all patients were discharged home. One patient developed new diabetes insipidus post-operatively. Patients who underwent endoscopic biopsy had decreased operative times and shorter hospitalizations. Biopsy for isolated pituitary stalk thickening for suspected germinoma is generally safe with high diagnostic utility. Importantly, 22% of presumed germinomas on imaging yielded alternative diagnoses on biopsy, adding support for pathology-proven data to guide treatment in relevant cases.
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http://dx.doi.org/10.1038/s41598-020-71988-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499298PMC
September 2020

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

J Am Soc Nephrol 2020 11 11;31(11):2653-2666. Epub 2020 Sep 11.

Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia.

Background: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.

Methods: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.

Results: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.

Conclusions: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

Clinical Trial Registry Name And Registration Number: Australian Clinical Trials Registry, ACTRN12610000650099.
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http://dx.doi.org/10.1681/ASN.2020040411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608977PMC
November 2020

Adverse effects of erenumab on cerebral proliferative angiopathy: A case report.

Cephalalgia 2021 Jan 19;41(1):122-126. Epub 2020 Aug 19.

Harvard Medical School, Boston, MA, USA.

Background: Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky.

Case: We describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits.

Conclusion: The evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.
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http://dx.doi.org/10.1177/0333102420950484DOI Listing
January 2021