Publications by authors named "Matthew Taylor"

662 Publications

Parkinsonism and Positive Dopamine Transporter Imaging in a Patient with a Novel KMT2B Variant.

Mov Disord Clin Pract 2021 Feb 2;8(2):279-281. Epub 2021 Feb 2.

Department of Neurology University of Colorado School of Medicine Aurora Colorado USA.

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http://dx.doi.org/10.1002/mdc3.13140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008275PMC
February 2021

Effect of Inactivation Methods on SARS-CoV-2 Virion Protein and Structure.

Viruses 2021 03 26;13(4). Epub 2021 Mar 26.

Department of Microbiology & Immunology, Montana State University, Bozeman, MT 59717, USA.

The risk posed by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) dictates that live-virus research is conducted in a biosafety level 3 (BSL3) facility. Working with SARS-CoV-2 at lower biosafety levels can expedite research yet requires the virus to be fully inactivated. In this study, we validated and compared two protocols for inactivating SARS-CoV-2: heat treatment and ultraviolet irradiation. The two methods were optimized to render the virus completely incapable of infection while limiting the destructive effects of inactivation. We observed that 15 min of incubation at 65 °C completely inactivates high titer viral stocks. Complete inactivation was also achieved with minimal amounts of UV power (70,000 µJ/cm), which is 100-fold less power than comparable studies. Once validated, the two methods were then compared for viral RNA quantification, virion purification, and antibody detection assays. We observed that UV irradiation resulted in a 2-log reduction of detectable genomes compared to heat inactivation. Protein yield following virion enrichment was equivalent for all inactivation conditions, but the quality of resulting viral proteins and virions were differentially impacted depending on inactivation method and time. Here, we outline the strengths and weaknesses of each method so that investigators might choose the one which best meets their research goals.
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http://dx.doi.org/10.3390/v13040562DOI Listing
March 2021

Genetics of dilated cardiomyopathy.

Curr Opin Cardiol 2021 May;36(3):288-294

Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora.

Purpose Of Review: Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM.

Recent Findings: Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown.

Summary: : The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.
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http://dx.doi.org/10.1097/HCO.0000000000000845DOI Listing
May 2021

Raising the bar for Randomized Trials involving Artificial Intelligence: The SPIRIT-AI and CONSORT-AI Guidelines.

J Invest Dermatol 2021 Mar 22. Epub 2021 Mar 22.

Division of Dermatology, Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.

Artificial intelligence (AI)-based applications have the potential to improve the quality and efficiency of patient care in dermatology. Unique challenges in the development and validation of these technologies may limit their generalizability and real-world applicability. Before widespread adoption of AI interventions, randomized trials should be conducted to evaluate their efficacy, safety, and cost effectiveness in clinical settings. The recent SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials - AI extension) and CONSORT-AI (Consolidated Standards of Reporting Trials - AI extension) guidance provide recommendations for reporting the methods and results of trials involving AI interventions. High-quality trials will provide gold standard evidence to support the adoption of AI for the benefit of patient care.
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http://dx.doi.org/10.1016/j.jid.2021.02.744DOI Listing
March 2021

Acute toxicity, accumulation and sublethal effects of four neonicotinoids on juvenile Black Tiger Shrimp (Penaeus monodon).

Chemosphere 2021 Feb 10;275:129918. Epub 2021 Feb 10.

Marine Ecology Research Centre, Southern Cross University, PO Box 157, Lismore, NSW, 2480, Australia; National Marine Science Centre, Southern Cross University, Coffs Harbour, NSW, 2450, Australia. Electronic address:

Neonicotinoid pesticides have been detected in aquatic habitats, and exposure may impact the health of aquatic organisms such as commercially-important crustaceans. Black Tiger Shrimp (Penaeus monodon) is a broadly distributed and high-value shrimp species that rely on estuaries for early life stages. Differences in the acute toxicity and accumulation of different neonicotinoids in tissues of commercial crustaceans have not been widely investigated. This study compared acute toxicity, uptake, and depuration of four neonicotinoids; thiamethoxam, clothianidin, acetamiprid, and imidacloprid, on juvenile P. monodon and their effects on enzyme biomarkers. Acute toxicity (48-h LC) was determined as 190 μg L (clothianidin), 390 μg L (thiamethoxam), 408 μg L (imidacloprid), and >500 μg L(acetamiprid). To assess uptake and elimination, shrimp were exposed to a fixed 5 μg L water concentration for eight days (uptake) or four days of exposure followed by four days of depuration (elimination). Neonicotinoid water and tissue concentrations were measured by liquid chromatography-mass spectrometry following solid-phase extraction and QuEChER extraction respectively. The lower toxicity associated with acetamiprid could be associated with lower accumulation in the tissue, with concentrations remaining below 0.01 μg g. The activity of acetylcholinesterase, catalase and glutathione S-transferase in abdominal tissues was determined by spectrophotometric assay, with significant sublethal effects detected for all four neonicotinoids. Depuration reduced the tissue concentration of the active ingredient and reduced the activity of oxidative stress enzymes. Given acetamiprid showed no acute toxicity and reduced impact on the enzymatic activity of P. monodon, it may be an appropriate alternative to other neonicotinoids in shrimp producing areas.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129918DOI Listing
February 2021

Correlation of Performance Status and Neutrophil-Lymphocyte Ratio With Efficacy in Radioiodine-Refractory Differentiated Thyroid Cancer Treated With Lenvatinib.

Thyroid 2021 Feb 26. Epub 2021 Feb 26.

Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States;

Background: Radioiodine-refractory differentiated thyroid cancer (RR-DTC) has a low 10-year patient-survival rate and is challenging to treat. Lenvatinib is a multikinase inhibitor approved for treatment of RR-DTC. This study aims to assess Eastern Cooperative Oncology Group performance status (ECOG PS) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for patients with RR-DTC treated with lenvatinib.

Methods: In this retrospective analysis of SELECT, patients randomly assigned to receive lenvatinib were classified according to baseline ECOG PS (0 or 1) or baseline NLR (≤3 or >3). The effects of baseline ECOG PS and NLR on progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated. Additionally, the effects of baseline ECOG PS on the change in diameter of target lesions and correlations between baseline NLR and the sum of the diameters of target lesions were calculated.

Results: Among patients who received lenvatinib, patients with a baseline ECOG PS of 0 had statistically improved PFS (hazard ratio [HR] 0.52 [95% confidence interval (CI): 0.35-0.77]; P=0.001), OS (HR 0.42 [95% CI: 0.26-0.69]; P=0.0004), and ORR (odds ratio [OR] 3.51 [95% CI: 2.02-6.10]; P<0.0001) compared with patients with a baseline ECOG PS of 1. Patients who received lenvatinib with a baseline NLR ≤3 also had improved PFS (HR 0.43 [95% CI: 0.29-0.65]; P<0.0001) and OS (HR 0.48 [95% CI: 0.29-0.78]; P=0.0029) versus patients with a baseline NLR >3. Moreover, patients with a baseline NLR ≤3 had a trend toward increased ORR (OR 1.57 [95% CI: 0.94-2.64]; P=0.08) compared to patients with a baseline NLR >3. Treatment-emergent adverse events were generally similar among patients who received lenvatinib, irrespective of patients' ECOG PS at baseline.

Conclusions: Lower ECOG PS and NLR may provide prognostic value for improved efficacy in patients with RR-DTC.  .
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http://dx.doi.org/10.1089/thy.2020.0779DOI Listing
February 2021

Maturation of Pluripotent Stem Cell-Derived Cardiomyocytes Enables Modeling of Human Hypertrophic Cardiomyopathy.

Stem Cell Reports 2021 Mar 25;16(3):519-533. Epub 2021 Feb 25.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940251PMC
March 2021

Thoracic Manifestations of inhalational injury caused by the Whakaari/White Island eruption.

J Med Imaging Radiat Oncol 2021 Feb 26. Epub 2021 Feb 26.

Department of Surgery, FMHS and Counties Manukau District Health Board, Auckland, New Zealand.

Introduction: Thoracic imaging of people who have survived exposure to a volcanic pyroclastic flow has not been described. In December 2019, an active volcano in New Zealand erupted with loss of life and severe burns to groups of people who were within one kilometre of a new fissure. Our aim was to describe the range of pulmonary abnormality in patients admitted to the Burns unit at Middlemore Hospital.

Methods: We describe the initial radiographic and computed tomography (CT) appearance of lung injuries in 14 people close to this fissure who were transported to our national burns centre in Middlemore hospital. We compared these appearances with bronchoscopy findings and A-a gradients as a measure of oxygen utilisation.

Results: All patients had chest radiographs and eight had CT scans within two days after admission. Nine had bronchoscopies within the first week. Two were repatriated to Australia, one of whom did not survive. Two died within 3 days after admission, and the remaining ten patients survived the first week. Eight patients required ongoing ventilation, seven of whom had abnormal CXRs or CT scans on admission. Two of these patients developed an ARDS pattern of oedema reflecting lung injury from the toxic surge but they recovered. In the five patients who survived the first week with relatively minor evidence of lung injury, bibasal atelectasis was the most common finding.

Conclusion: Pyroclastic flow effect caused a variety of lung abnormalities most likely due to toxic gas emissions. Upper airway burns were seen at bronchoscopy in only 5 patients. An ARDS response in the lungs of two patients improved within three months.
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http://dx.doi.org/10.1111/1754-9485.13159DOI Listing
February 2021

Migration histories and perfluoroalkyl acid (PFAA) loads in an estuarine fish: A novel union of analyses to understand variation in contaminant concentrations.

Environ Pollut 2021 May 7;276:116686. Epub 2021 Feb 7.

The University of Queensland, Queensland Alliance for Environmental Health Sciences, 20 Cornwall Street, Woolloongabba, Queensland, 4102, Australia.

Previous studies have shown that accumulation of perfluoroalkyl acids (PFAAs) in the tissues of aquatic species is highly variable. Movement and migration patterns in these species represent an important consideration when evaluating contaminant accumulation in exposed biota, and may have a large influence on the risk profiles for migratory seafood species. In this study, relationships between PFAA concentrations in muscle and liver tissue, and recent fish migration history (inferred from metals profiles in fish otoliths, otherwise known as otolith chemistry) were evaluated in Sea Mullet (Mugil cephalus). A greater number of PFAAs, and higher concentrations, were found in liver compared to muscle tissue. Perfluorooctane sulfonate (PFOS) was present in highest concentrations in both muscle and liver tissues, and there was strong correlation in concentrations between these two tissues. PFOS was found to decrease and increase alongside recent strontium and barium concentrations (respectively) in the otolith, suggesting higher concentrations of PFAAs in fish recently exposed to comparatively lower salinity environments. This study highlights how otolith chemistry can be employed to examine links between contaminant concentrations in fish, and their recent migration history. This approach shows promise for studying contaminant residues in mobile seafood species within the natural environment.
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http://dx.doi.org/10.1016/j.envpol.2021.116686DOI Listing
May 2021

An unusual distribution of herpes zoster mandibularis post total parotidectomy.

Int J Infect Dis 2021 Feb 11. Epub 2021 Feb 11.

Department of Otolaryngology, Head and Neck Surgery, Monash Health, Clayton, Victoria, Australia; Department of Otolaryngology, Head and Neck Surgery, Alfred Health, Melbourne, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.

This case report highlights an unusual presentation of herpes zoster mandibularis in an immunocompromised patient with previous head and neck surgery, with relative sparing of the cheek. It demonstrates the importance of critically considering past medical and surgical history in clinical diagnosis and management of the disease.
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http://dx.doi.org/10.1016/j.ijid.2021.02.008DOI Listing
February 2021

Long-term movements and activity patterns of platypus on regulated rivers.

Sci Rep 2021 Feb 11;11(1):3590. Epub 2021 Feb 11.

Centre for Ecosystem Science, School of Biological, Earth & Environmental Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

The platypus is a semi-aquatic mammal, endemic to freshwater habitats of eastern Australia. There are gaps in the understanding of platypus movement behaviour within river systems, including spatial and temporal organization of individuals. We tracked movements of 12 platypuses on the regulated Snowy and Mitta Mitta Rivers for up to 12-months, the longest continuous tracking of platypus using acoustic telemetry. Platypuses remained relatively localized, occupying 0.73-8.45 km of river over 12 months, consistent with previous tracking studies over shorter periods. Males moved further than females, and larger males had higher cumulative movements, suggesting a possible relationship to metabolic requirements. Platypuses moved greater distances on the Mitta Mitta River, possibly associated with impacts of altered flow regimes to their macroinvertebrate diet. Increased movements and diurnal activity during winter were primarily driven by males, possibly attributable to breeding behaviours, rather than increased costs of winter foraging. Evidence for relatively small movements has implications for declining populations, given areas of localised declines are unlikely to be supplemented by migrating platypuses, especially when dispersal is restricted by dam walls. Understanding platypus movement behaviour is pertinent for their conservation, as water resource development and habitat modification continue to reduce connectivity between populations across their distribution.
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http://dx.doi.org/10.1038/s41598-021-81142-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878892PMC
February 2021

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

EClinicalMedicine 2021 Jan 23;31:100693. Epub 2020 Dec 23.

Uniformed Services University F. Edward Hebert School of Medicine in Bethesda, Maryland, United States.

Background: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting.

Methods: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings.

Findings: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)).

Interpretation: Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations.

Funding: This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13-043-01) https://www.cancer.org/ (SH; BS).
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http://dx.doi.org/10.1016/j.eclinm.2020.100693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846671PMC
January 2021

Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer.

Cancer Res 2021 Feb 1. Epub 2021 Feb 1.

Radiation Oncology, University of Colorado Denver

Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3892DOI Listing
February 2021

Assessing the importance of interleukin-6 in COVID-19 - Authors' reply.

Lancet Respir Med 2021 02 15;9(2):e14-e15. Epub 2021 Jan 15.

Feinstein Institute for Medical Research, Manhasset, NY, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY, USA; Zucker School of Medicine at Hofstra-Northwell, New York, NY, USA.

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http://dx.doi.org/10.1016/S2213-2600(20)30603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834405PMC
February 2021

Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms.

Biochem J 2021 Feb;478(3):553-578

Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

Autosomal dominant mutations in LRRK2 that enhance kinase activity cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases including Rab8A and Rab10 within its effector binding motif. Here, we explore whether LRRK1, a less studied homolog of LRRK2 that regulates growth factor receptor trafficking and osteoclast biology might also phosphorylate Rab proteins. Using mass spectrometry, we found that in LRRK1 knock-out cells, phosphorylation of Rab7A at Ser72 was most impacted. This residue lies at the equivalent site targeted by LRRK2 on Rab8A and Rab10. Accordingly, recombinant LRRK1 efficiently phosphorylated Rab7A at Ser72, but not Rab8A or Rab10. Employing a novel phospho-specific antibody, we found that phorbol ester stimulation of mouse embryonic fibroblasts markedly enhanced phosphorylation of Rab7A at Ser72 via LRRK1. We identify two LRRK1 mutations (K746G and I1412T), equivalent to the LRRK2 R1441G and I2020T Parkinson's mutations, that enhance LRRK1 mediated phosphorylation of Rab7A. We demonstrate that two regulators of LRRK2 namely Rab29 and VPS35[D620N], do not influence LRRK1. Widely used LRRK2 inhibitors do not inhibit LRRK1, but we identify a promiscuous inhibitor termed GZD-824 that inhibits both LRRK1 and LRRK2. The PPM1H Rab phosphatase when overexpressed dephosphorylates Rab7A. Finally, the interaction of Rab7A with its effector RILP is not affected by LRRK1 phosphorylation and we observe that maximal stimulation of the TBK1 or PINK1 pathway does not elevate Rab7A phosphorylation. Altogether, these findings reinforce the idea that the LRRK enzymes have evolved as major regulators of Rab biology with distinct substrate specificity.
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http://dx.doi.org/10.1042/BCJ20200937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886321PMC
February 2021

Do gastroenterologists have medical inertia towards coeliac disease? A UK multicentre secondary care study.

BMJ Open Gastroenterol 2021 Jan;8(1)

The University of Sheffield Medical School, Sheffield, UK

Objective: This study aimed to assess if there is secondary care medical inertia towards coeliac disease (CD).

Design: Group (1): Time from primary care presentation to diagnostic endoscopy was quantified in 151 adult patients with a positive endomysial antibody test and compared with 92 adult patients with histologically proven inflammatory bowel disease (IBD). Group (2): Across four hospitals, duodenal biopsy reports for suspected CD were reviewed (n=1423). Group (3): Clinical complexity was compared between known CD (n=102) and IBD (n=99) patients at their respective follow-up clinic appointments. Group (4): 50 gastroenterologists were questioned about their perspective on CD and IBD.

Results: Group (1): Suspected coeliac patients waited significantly longer for diagnostic endoscopy following referral (48.5 (28-89) days) than suspected patients with IBD (34.5 (18-70) days; p=0.003). Group (2): 1423 patients underwent diagnostic endoscopy for possible CD, with only 40.0% meeting guidelines to take four biopsies. Increased diagnosis of CD occurred if guidelines were followed (10.1% vs 4.6% p<0.0001). 12.4% of newly diagnosed CD patients had at least one non-diagnostic gastroscopy in the 5 years prior to diagnosis. Group (4): 32.0% of gastroenterologists failed to identify that CD has greater prevalence in adults than IBD. Moreover, 36.0% of gastroenterologists felt that doctors were not required for the management of CD.

Conclusion: Prolonged waiting times for endoscopy and inadequacies in biopsy technique were demonstrated suggesting medical inertia towards CD. However, this has to be balanced against rationalising care accordingly. A Coeliac UK National Patient Charter may standardise care across the UK.
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http://dx.doi.org/10.1136/bmjgast-2020-000544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813426PMC
January 2021

Mediastinal IgG4-Related Disease Presenting As Superior Vena Cava Syndrome.

Ann Thorac Surg 2021 Jan 4. Epub 2021 Jan 4.

Division of Thoracic Surgery, Department of Surgery, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033. Electronic address:

IgG4-related disease (IgG4-RD) was first identified as a systemic condition in 2003 when extra-pancreatic manifestations were identified in patients with autoimmune pancreatitis. Its peak incidence occurs in the fifth or sixth decades of life. Isolated extra-aortic mediastinal involvement is extremely rare. We report a case of isolated extra-aortic mediastinal IgG4-RD encasing the superior vena cava (SVC), manifesting as SVC syndrome in a 25-year-old man with no personal or family history of autoimmune disease. Resection with SVC reconstruction was performed.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.064DOI Listing
January 2021

Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish.

Hum Mutat 2020 Dec 31. Epub 2020 Dec 31.

Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole-exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7 embryos, although alterations were seen in Hh pathway gene expression. This study suggests defects in KIF7-dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.
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http://dx.doi.org/10.1002/humu.24162DOI Listing
December 2020

Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites.

Biochem J 2021 01;478(2):299-326

Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.

Mutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplexed targeted mass spectrometry assay to quantify endogenous levels of LRRK2-phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and LRRK2-phosphorylated at the Ser910 and Ser935 biomarker sites. Exploiting this assay, we quantify for the first time the relative levels of each of the pRab proteins in different cells (mouse embryonic fibroblasts, human neutrophils) and mouse tissues (brain, kidney, lung and spleen). We define how these components are impacted by Parkinson's pathogenic mutations (LRRK2[R1441C] and VPS35[D620N]) and LRRK2 inhibitors. We find that the VPS35[D620N], but not LRRK2[R1441C] mutation, enhances Rab1 phosphorylation in a manner blocked by administration of an LRRK2 inhibitor, providing the first evidence that endogenous Rab1 is a physiological substrate for LRRK2. We exploit this assay to demonstrate that in Parkinson's patients with VPS35[D620N] mutations, phosphorylation of multiple Rab proteins (Rab1, Rab3, Rab8, Rab10 and Rab43) is elevated. We highlight the benefits of this assay over immunoblotting approaches currently deployed to assess LRRK2 Rab signalling pathway.
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http://dx.doi.org/10.1042/BCJ20200930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833208PMC
January 2021

Characteristics and risk factors associated with critical illness in pediatric COVID-19.

Ann Intensive Care 2020 Dec 19;10(1):171. Epub 2020 Dec 19.

Division of Pediatric Critical Care Medicine, Steven and Alexandra Cohen Children's Medical Center of New York, Northwell Health, Donald and Barbara Zucker School of Medicine At Hofstra/Northwell, 269-01 76th Ave, New Hyde Park, NY, 11040, USA.

Background: While much has been reported regarding the clinical course of COVID-19 in children, little is known regarding factors associated with organ dysfunction in pediatric COVID-19. We describe critical illness in pediatric patients with active COVID-19 and identify factors associated with PICU admission and organ dysfunction. This is a retrospective chart review of 77 pediatric patients age 1 day to 21 years admitted to two New York City pediatric hospitals within the Northwell Health system between February 1 and April 24, 2020 with PCR + SARS-CoV-2. Descriptive statistics were used to describe the hospital course and laboratory results and bivariate comparisons were performed on variables to determine differences.

Results: Forty-seven patients (61%) were admitted to the general pediatric floor and thirty (39%) to the PICU. The majority (97%, n = 75) survived to discharge, 1.3% (n = 1) remain admitted, and 1.3% (n = 1) died. Common indications for PICU admission included hypoxia (50%), hemodynamic instability (20%), diabetic ketoacidosis (6.7%), mediastinal mass (6.7%), apnea (6.7%), acute chest syndrome in sickle cell disease (6.7%), and cardiac dysfunction (6.7%). Of PICU patients, 46.7% experienced any significant organ dysfunction (pSOFA >  = 2) during admission. Patients aged 12 years or greater were more likely to be admitted to a PICU compared to younger patients (p = 0.015). Presence of an underlying comorbidity was not associated with need for PICU admission (p = 0.227) or organ dysfunction (p = 0.87). Initial white blood cell count (WBC), platelet count, and ferritin were not associated with need for PICU admission. Initial C-reactive protein was associated with both need for PICU admission (p = 0.005) and presence of organ dysfunction (p = 0.001). Initial WBC and presenting thrombocytopenia were associated with organ dysfunction (p = 0.034 and p = 0.003, respectively).

Conclusions: Age over 12 years and initial CRP were associated with need for PICU admission in COVID-19. Organ dysfunction was associated with elevated admission CRP, elevated WBC, and thrombocytopenia. These factors may be useful in determining risk for critical illness and organ dysfunction in pediatric COVID-19.
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http://dx.doi.org/10.1186/s13613-020-00790-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749393PMC
December 2020

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model.

Front Immunol 2020 20;11:563402. Epub 2020 Nov 20.

The Division of Critical Care Medicine, Department of Pediatrics, The Feinstein Institutes for Medical Research, Manhasset, NY, and Cohen Children's Medical Center/Northwell Health, New Hyde Park, NY, United States.

The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term "immune education." These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8 mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.
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http://dx.doi.org/10.3389/fimmu.2020.563402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715000PMC
November 2020

Outpatient prescribing of opioids to adults diagnosed with mental disorders in the United States.

Drug Alcohol Depend 2021 Feb 23;219:108414. Epub 2020 Nov 23.

Rutgers Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, 112 Paterson St., New Brunswick, NJ, 08901, USA; Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. Electronic address:

Background: Adults with mood and anxiety disorders have an increased likelihood of being prescribed opioids. The influence of other mental disorders, such as psychotic and attention disorders, on opioid prescribing patterns is less known.

Methods: We studied a population-representative sample of 166,927 outpatient visits for adults with painful conditions from the 2002-2016 National Ambulatory Medical Care Survey and the 2002-2011 National Hospital Ambulatory Medical Care Survey. Logistic regression analyses examined the likelihood of opioid prescription among visits with specific mental disorder diagnoses (anxiety, attention, mood, psychotic, post-traumatic stress disorder (PTSD), opioid use, and non-opioid substance use), adjusted for covariates and weighted for the complex survey design. Secondary analyses stratified results by whether opioids were newly initiated or continued.

Results: Opioids were prescribed at 16.8 % of visits. Mood, anxiety, and non-opioid substance use disorders were associated with higher likelihoods of opioid prescriptions, particularly for continued rather than first-time prescriptions. Psychotic disorders were strongly negatively associated with opioid prescriptions (adjusted odds ratio 0.44, 95 % CI 0.22-0.86). Diagnoses of PTSD and attention disorders were not associated with opioid prescribing.

Conclusions: Outpatient physicians are more likely to prescribe and refill opioids for adults with pain who present with mood, anxiety, and non-opioid substance use disorders, but not for those who present with PTSD or attention disorders. Patients with psychotic disorders and pain are markedly less likely to be prescribed opioids.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108414DOI Listing
February 2021

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors.

Future Oncol 2021 Feb 10;17(6):637-648. Epub 2020 Dec 10.

The START Center for Cancer Care, San Antonio, TX 78229, USA.

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0937DOI Listing
February 2021

Establishing trust within interprofessional teams with a novel simulation activity in the pediatric clerkship.

J Interprof Care 2020 Dec 8:1-6. Epub 2020 Dec 8.

Pediatrics, Harvard Medical School , Boston, MA, USA.

Interprofessional trust is essential for effective team-based care. Medical students are transient members of clinical teams during clerkship rotations and there may be limited focus on developing competency in interprofessional collaboration. Within a pediatric clerkship rotation, we developed a novel simulation activity involving an interprofessional conflict, aiming to foster trusting interprofessional relationships. Active participants included a nurse educator and a medical student participant, with additional students using a checklist to actively observe. The debrief focused on teaching points related to interprofessional competencies and conflict resolution. Students completed a written evaluation immediately following the simulation. Descriptive statistics were used to analyze Likert-type scale questions. Conventional content analysis was used to analyze open-ended responses. Two hundred and fourteen students participated in the simulation between June 2018-June 2019. Most students indicated that the simulation was effective (86%) and improved their confidence to constructively manage disagreements about patient care (88%). Students described anticipated changes in practice including developing their role on the interprofessional team as a medical student, developing a shared mental model, and establishing a shared goal. Our findings suggest that simulation-based learning may present an opportunity for developing interprofessional trust in academic health centers.
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http://dx.doi.org/10.1080/13561820.2020.1840338DOI Listing
December 2020

Diagnosis at gut point: rapid identification of pneumoperitoneum via point-of-care ultrasound.

Ultrasound J 2020 Dec 7;12(1):52. Epub 2020 Dec 7.

Department of Internal Medicine, Prisma Health Midlands, University of South Carolina School of Medicine, Columbia, SC, 29209, USA.

Undifferentiated abdominal pain is a common presentation often requiring immediate medical or surgical intervention. Providing an accurate diagnosis involves a detailed patient history and thorough physical exam. Point of care ultrasound is gaining acceptance as a rapid diagnostic tool that can be used to accurately detect life-threatening conditions while potentially avoiding unnecessary radiation exposure and facilitating rapid treatment. Detection of pneumoperitoneum with point-of-care ultrasound is a simple procedure that relies heavily on the experience of the investigating practitioner. Standard technique involves placing a high-frequency linear-array transducer in the right upper quadrant, where abdominal free air is most likely to accumulate. Detection of the 'gut point', which is the transition of abdominal wall sliding to lack thereof in a single image, is the pathognomonic finding of pneumoperitoneum. If visualization is difficult, moving the patient to the left lateral decubitus position or using the scissors technique can provide additional image views. This representative case report and review highlights the use of abdominal POCUS for the diagnosis of pneumoperitoneum. Ultrasound should continue to be explored by clinicians to narrow the differential diagnosis of acute abdominal pain.
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http://dx.doi.org/10.1186/s13089-020-00195-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721848PMC
December 2020

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

Lancet Oncol 2020 12;21(12):e575-e588

School of Nursing and Milken Institute School of Public Health, George Washington University, Washington, DC, USA.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.
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http://dx.doi.org/10.1016/S1470-2045(20)30485-XDOI Listing
December 2020

Trial of a novel experimental design to test depuration of PFASs from the edible tissues of Giant Mud Crab following exposure under natural conditions in the wild.

Sci Total Environ 2021 Mar 20;758:143650. Epub 2020 Nov 20.

RPS AAP Consulting Pty Ltd, 255 Pitt St, Sydney, NSW 2000, Australia.

Poly and perfluorinated alkyl substances (PFASs) are persistent organic pollutants (POPs) that are highly resistant to environmental degradation, and have been detected in a broad range of terrestrial and aquatic species. Portunid crabs have been shown to accumulate comparatively high concentrations of PFASs, but previous work examining depuration in crabs was inconclusive. Here, we trialled a novel experimental design to study depuration of PFASs from edible tissues of portunid crabs, using paired claw samples, and trial this design with Giant Mud Crab Scylla serrata exposed to the contaminant under natural conditions. We found evidence for depuration of perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorooctanoic acid (PFOA), but with depuration half-lives as high as 40 days (for PFOS). We also observed substantial variability in the data, including differences in PFAS concentrations between claws from the same individuals, potentially resulting from claw loss and re-growth prior to capture. These results have broad implications for assessing and minimising exposure risk in seafood species.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143650DOI Listing
March 2021

Animal size impacts perfluoroalkyl acid (PFAA) concentrations in muscle tissue of estuarine fish and invertebrate species.

Authors:
Matthew D Taylor

Environ Pollut 2020 Dec 6;267:115595. Epub 2020 Sep 6.

Port Stephens Fisheries Institute, New South Wales Department of Primary Industries, Locked Bag 1, Nelson Bay, NSW, 2315, Australia; The University of Queensland, Queensland Alliance for Environmental Health Sciences, 20 Cornwall Street, Woolloongabba, Queensland, 4102, Australia. Electronic address:

Environmental emissions of perfluoroalkyl acids (PFAAs) often contaminate aquatic ecosystems and accumulate in the species therein. This can represent an exposure pathway for human populations where seafood is consumed. Concentrations of PFAAs in water breathing animals may be a function of many different factors, however, little is known about how these different factors impact contaminant accumulation in estuarine and marine species. This study explores the relationships between PFAA accumulation and two key variables, animal size and sediment concentrations, for a number of important seafood species. Sixty Dusky Flathead (Platycephalus fuscus), 58 Mulloway (Argyrosomus japonicus) and 53 Giant Mud Crab (Scylla serrata) were tested for perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonate (PFHxS) in edible tissues, and the concentrations compared with animal size and sediment concentrations at the location of capture. PFAAs showed a high degree of variation among species, and PFOA and PFHxS were only common in Giant Mud Crab. Log-transformed PFOS concentrations in all three species showed negative correlations with animal size (weight). There was limited evidence for relationships between PFOS muscle tissue concentration and sediment PFOS concentration. The patterns observed are potentially explained by changes in trophic position, relative growth rate, consumption rate and metabolic rate, throughout the species life history. The results contrast with observations for other persistent organic pollutants, whereby larger individuals tend to carry greater contaminant loads. Future work is required to establish whether these patterns are evident for PFAAs in other species and contaminant sources.
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http://dx.doi.org/10.1016/j.envpol.2020.115595DOI Listing
December 2020

Pain Severity and Management of Hidradenitis Suppurativa at US Emergency Department Visits.

JAMA Dermatol 2021 01;157(1):115-117

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.

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http://dx.doi.org/10.1001/jamadermatol.2020.4494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675211PMC
January 2021

Acute on Chronic Heart Failure Secondary to Left Ventricular Noncompaction.

Case Rep Pediatr 2020 26;2020:6369806. Epub 2020 Oct 26.

Cohen's Children's Medical Center, Northwell Health, New Hyde Park, NY, USA.

Left ventricular noncompaction (LVNC) is a rare cardiomyopathy characterized by hypertrabeculations and intertrabecular recesses most often seen in the left ventricle (LV). The patient may be asymptomatic or present with heart failure, arrhythmia, and sudden death. We discuss a previously healthy 7-year-old male who presented to the Emergency Department (ED) multiple times over a three-week period. His complaints evolved over the course of his illness, initially presenting with fatigue and suicidal ideation, followed by diffuse abdominal pain. Prior to his ICU admission, he had been discharged from the ED twice, due to well appearance and reassuring lab findings. He returned to the ED a final time with severe venous congestion and cardiogenic shock with acute hepatic injury. Echocardiogram revealed LV apical hypertrabeculation with a severe dilated cardiomyopathy and biventricular failure along with a large thrombus in the left ventricular cavity. Congestive heart failure and anticoagulation therapy was initiated, and the patient went on to biventricular assist device (BiVAD) placement and cardiac transplant. Although LVNC is rare, pediatric heart failure does present to the general pediatrician and has high morbidity and mortality. The presenting symptoms can be obscure and pose a challenge to pediatricians. This case report and review will assist in familiarizing the general pediatrician with pediatric heart failure presentation, treatment, and course.
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http://dx.doi.org/10.1155/2020/6369806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605943PMC
October 2020