Publications by authors named "David Wilson"

2,641 Publications

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Away Rotation Applications in Emergency Medicine: Medical Student Behaviors, Outcomes, and Stressors.

J Emerg Med 2022 Jan 22. Epub 2022 Jan 22.

Department of Emergency Medicine, University of Massachusetts Medical School - Baystate Medical Center, Springfield, Massachusetts.

Background: Completing an emergency medicine (EM) away rotation is integral to matching successfully into an EM residency program. The demand for EM away rotations (ARs) drives students to submit numerous applications without evidence-based recommendations to guide stakeholders on the approach or number to submit.

Objectives: We conducted a survey study of EM-bound fourth-year medical students to gain insight into their AR application experiences, outcomes, and perceptions.

Methods: We distributed a 40-item questionnaire to EM applicants in Fall 2018 via e-mail through the Clerkship Directors in Emergency Medicine, Council of Residency Directors in EM, and Emergency Medicine Residents' Association listservs. Responses were evaluated using quantitative and qualitative analysis. Primary outcomes were the number of AR applications submitted and AR offers received by students. Secondary outcomes were students' self-assessment of their competitiveness, differences in AR application numbers by degree type, sources of student advising, and student perceptions of the AR application process.

Results: There were 253 respondents, consisting of 192 allopathic (MD) and 61 osteopathic (DO) medical students, who met the inclusion criteria, representing about 10% of the applicant pool. On average, students submitted 13.97 applications (95% confidence interval [CI] 11.59-16.35), received 3.25 offers (95% CI 3.01-3.49), and accepted 2.22 offers (95% CI 2.08-2.36). DO candidates submitted twice as many applications as MD candidates while experiencing a similar rate of offers received. Peer influence (n = 154, 61%), peer online advising networks (n = 83, 33%), and self-assessment (n = 114, 45%) were the most often reported causes of increased applications; cost (n = 104, 41%) and geographic limitations (n = 114, 45%) were the most often reported causes of decreased applications. Open-response analysis revealed frustration with lack of standardization (n = 44, 29.5%), insufficient transparency on available positions (n = 37, 24.8%), limited communication (n = 30, 20.1%), and cost (n = 12, 8.1%).

Conclusions: This study showed that, as a whole, students received one away rotation offer for every four to five applications submitted. It clarified factors contributing to increased EM away rotation application submissions and associated stressors inherent in the application experience. Our findings offer insights to inform advising recommendations. They also suggest that stakeholders consider standardizing the process and improve communication over spot availability and application status.
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http://dx.doi.org/10.1016/j.jemermed.2021.11.008DOI Listing
January 2022

In vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinoma.

Cancer Res 2022 Jan 24. Epub 2022 Jan 24.

MRC Human Genetics Unit, University of Edinburgh

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacological co-inhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2556DOI Listing
January 2022

A Systematic Review and Meta-Analysis of Efficacy of Botulinum Toxin A for Neuropathic Pain.

Toxins (Basel) 2022 Jan 3;14(1). Epub 2022 Jan 3.

National Health and Medical Research Council Centre of Research Excellence in Frailty and Healthy Aging, Basil Hetzel Institute, 28 Woodville Road, Adelaide, SA 5011, Australia.

We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) conducted from January 2005 to June 2021 to update the evidence of Botulinum toxin A (BoNT-A) in neuropathic pain (NP) in addition to quality of life (QOL), mental health, and sleep outcomes. We conducted a Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria analysis of RCTs from the following data sources: EMBASE, CINAHL, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane database, Cochrane Clinical Trial Register, Australia New Zealand Clinical Trials Registry, and EU Clinical Trials Register. Meta-analysis of 17 studies showed a mean final VAS reduction in pain in the intervention group of 2.59 units (95% confidence interval: 1.79, 3.38) greater than the mean for the placebo group. The overall mean difference for sleep, Hospital Anxiety and Depression Scale (HADS) anxiety, HADS depression, and QOL mental and physical sub-scales were, respectively, 1.10 (95% CI: -1.71, 3.90), 1.41 (95% CI: -0.61, 3.43), -0.16 (95% CI: -1.95, 1.63), 0.85 (95% CI: -1.85, 3.56), and -0.71 (95% CI: -3.39, 1.97), indicating no significance. BoNT-A is effective for NP; however, small-scale RCTs to date have been limited in evidence. The reasons for this are discussed, and methods for future RCTs are developed to establish BoNT-A as the first-line agent.
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http://dx.doi.org/10.3390/toxins14010036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780616PMC
January 2022

Nuclei Detection for 3D Microscopy With a Fully Convolutional Regression Network.

IEEE Access 2021 19;9:60396-60408. Epub 2021 Apr 19.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.

Advances in three-dimensional microscopy and tissue clearing are enabling whole-organ imaging with single-cell resolution. Fast and reliable image processing tools are needed to analyze the resulting image volumes, including automated cell detection, cell counting and cell analytics. Deep learning approaches have shown promising results in two- and three-dimensional nuclei detection tasks, however detecting overlapping or non-spherical nuclei of different sizes and shapes in the presence of a blurring point spread function remains challenging and often leads to incorrect nuclei merging and splitting. Here we present a new regression-based fully convolutional network that located a thousand nuclei centroids with high accuracy in under a minute when combined with V-net, a popular three-dimensional semantic-segmentation architecture. High nuclei detection F1-scores of 95.3% and 92.5% were obtained in two different whole quail embryonic hearts, a tissue type difficult to segment because of its high cell density, and heterogeneous and elliptical nuclei. Similar high scores were obtained in the mouse brain stem, demonstrating that this approach is highly transferable to nuclei of different shapes and intensities. Finally, spatial statistics were performed on the resulting centroids. The spatial distribution of nuclei obtained by our approach most resembles the spatial distribution of manually identified nuclei, indicating that this approach could serve in future spatial analyses of cell organization.
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http://dx.doi.org/10.1109/ACCESS.2021.3073894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751907PMC
April 2021

Engineered modular heterocyclic-diamidines for sequence-specific recognition of mixed AT/GC base pairs at the DNA minor groove.

Chem Sci 2021 Dec 2;12(48):15849-15861. Epub 2021 Nov 2.

Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University 50 Decatur St SE Atlanta GA 30303 USA +1 404-413-5503.

This report describes a breakthrough in a project to design minor groove binders to recognize any sequence of DNA. A key goal is to invent synthetic chemistry for compound preparation to recognize an adjacent GG sequence that has been difficult to target. After trying several unsuccessful compound designs, an -alkyl-benzodiimidazole structure was selected to provide two H-bond acceptors for the adjacent GG-NH groups. Flanking thiophenes provide a preorganized structure with strong affinity, DB2831, and the structure is terminated by phenyl-amidines. The binding experimental results for DB2831 with a target AAAGGTTT sequence were successful and include a high Δ , biosensor SPR with a of 4 nM, a similar from fluorescence titrations and supporting competition mass spectrometry. MD analysis of DB2831 bound to an AAAGGTTT site reveals that the two unprotonated of the benzodiimidazole group form strong H-bonds (based on distance) with the two central G-NH while the central -CH of the benzodiimidazole is close to the -C[double bond, length as m-dash]O of a C base. These three interactions account for the strong preference of DB2831 for a -GG- sequence. Surprisingly, a complex with one dynamic, interfacial water is favored with 75% occupancy.
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http://dx.doi.org/10.1039/d1sc04720eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672716PMC
December 2021

Personalized subcutaneous implantable cardioverter-defibrillator sensing vectors generated by mathematical rotation increase device eligibility whilst preserving device performance.

Europace 2022 Jan 11. Epub 2022 Jan 11.

Faculty of Medicine, University of Southampton, Southampton, UK.

Aims: Approximately 5.7% of potential subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients are ineligible by virtue of their vector morphology, with higher rates of ineligibility observed in some at-risk groups. Mathematical vector rotation is a novel technique that can generate a personalized sensing vector, one with maximal R:T ratio, using electrocardiogram (ECG) signal recorded from the present S-ICD location.

Methods And Results: A cohort of S-ICD ineligible patients were identified through ECG screening of ICD patients with no ventricular pacing requirement and their personalized vectors were generated using ECG signal from a Holter monitor. Subcutaneous ICD eligibility in this cohort was then recalculated. In a separate cohort, episodes of arrhythmia were recorded in patients undergoing arrhythmia induction, and arrhythmia detection in standard S-ICD vectors was compared to rotated vectors using an S-ICD simulator. Ninety-two participants (mean age 64.9 ± 2.7 years) underwent screening and 5.4% were found to be S-ICD ineligible. Personalized vector generation increased the R:T ratio in these vectors from 2.21 to 7.21 (4.54-9.88, P < 0.001) increasing the cohort eligibility from 94.6% to 100%. Rotated S-ICD vectors also showed high ventricular fibrillation (VF) detection sensitivity (97.8%), low time to VF detection (6.1 s), and excellent tachycardia discrimination (sensitivity 96%, specificity 88%), with no significant differences between rotated and standard vectors.

Conclusion: In S-ICD ineligible patients, mathematical vector rotation can generate a personalized vector that is associated with a significant increase in R:T ratio, resulting in universal device eligibility in our cohort. Ventricular fibrillation detection efficacy, time to VF detection, and tachycardia discrimination were not affected by vector rotation.
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http://dx.doi.org/10.1093/europace/euab310DOI Listing
January 2022

Non-Invasive Imaging in the Evaluation of Cardiac Allograft Vasculopathy in Heart Transplantation: A Systematic Review.

Curr Probl Cardiol 2022 Jan 8:101103. Epub 2022 Jan 8.

Department of Medicine, University Hospitals, Cleveland, Ohio; Harrington Heart and Vascular Institute, University Hospitals and School of Medicine, Case Western Reserve University, Cleveland, Ohio. Electronic address:

Cardiac allograft vasculopathy (CAV) is the leading cause of long-term graft dysfunction in patients with heart transplantation and is linked with significant morbidity and mortality. Currently, the gold standard for diagnosing CAV is coronary imaging with intravascular ultrasound (IVUS) during traditional invasive coronary angiography (ICA). Invasive imaging, however, carries increased procedural risk and expense to patients in addition to requiring an experienced interventionalist. With the improvements in non-invasive cardiac imaging modalities such as transthoracic echocardiography (TTE), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET), an alternative non-invasive imaging approach for the early detection of CAV may be feasible. In this systematic review, we explored the literature to investigate the utility of non-invasive imaging in diagnosis of CAV in >3000 patients across 49 studies. We also discuss the strengths and weaknesses for each imaging modality. Overall, all four imaging modalities show good to excellent accuracy for identifying CAV with significant variations across studies. Majority of the studies compared non-invasive imaging with ICA without intravascular imaging. In summary, non-invasive imaging modalities offer an alternative approach to invasive coronary imaging for CAV. Future studies should investigate longitudinal non-invasive protocols in low-risk patients after heart transplantation.
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http://dx.doi.org/10.1016/j.cpcardiol.2022.101103DOI Listing
January 2022

Air-Stable Thermoluminescent Carbodicarbene-Borafluorenium Ions.

J Am Chem Soc 2022 Jan 4;144(1):590-598. Epub 2022 Jan 4.

Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States.

Borenium ions, originally synthesized as fundamentally important laboratory curiosities, have attracted significant attention due to their applications in catalysis and frustrated Lewis pair chemistry. However, investigations of the materials properties of these types of compounds are exceptionally rare. Herein, we report the synthesis, molecular structures, and optical properties of a new class of air-stable borenium ions, stabilized by the strongly donating carbodicarbene (CDC) ligand (, , ). Notably, CDC-borafluorenium ions exhibit thermoluminescence in solution, a result of a twisted intramolecular charge transfer process. The temperature responsiveness, which is observable by the naked eye, is assessed over a 20 to -60 °C range. Significantly, compound emits white light at lower temperatures. In the solid state, these borocations exhibit increased quantum yields due to aggregation-induced emission. CDC-borafluorenium ions with two different counteranions (Br, BPh) were investigated to evaluate the effect of anion size on the solution and solid-state optical properties. In addition, CDCs containing both symmetrical and unsymmetrical N-heterocycles (bis(1-isopropyl-3-methylbenzimidazol-2-ylidene)methane and bis(1,3-dimethyl-1,3-dihydro-2-benzo[]imidazol-2-ylidene)methane) were tested to understand the implications of free rotation about the CDC ligand carbon-carbon bonds. The experimental work is complemented by a comprehensive theoretical analysis of the excited-state dynamics.
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http://dx.doi.org/10.1021/jacs.1c11861DOI Listing
January 2022

11C-Para-aminobenzoic acid PET imaging of S. aureus and MRSA infection in preclinical models and humans.

JCI Insight 2022 Jan 11;7(1). Epub 2022 Jan 11.

Center for Infection and Inflammation Imaging Research and.

Tools for noninvasive detection of bacterial pathogens are needed but are not currently available for clinical use. We have previously shown that para-aminobenzoic acid (PABA) rapidly accumulates in a wide range of pathogenic bacteria, motivating the development of related PET radiotracers. In this study, 11C-PABA PET imaging was used to accurately detect and monitor infections due to pyogenic bacteria in multiple clinically relevant animal models. 11C-PABA PET imaging selectively detected infections in muscle, intervertebral discs, and methicillin-resistant Staphylococcus aureus-infected orthopedic implants. In what we believe to be first-in-human studies in healthy participants, 11C-PABA was safe, well-tolerated, and had a favorable biodistribution, with low background activity in the lungs, muscles, and brain. 11C-PABA has the potential for clinical translation to detect and localize a broad range of bacteria.
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http://dx.doi.org/10.1172/jci.insight.154117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765043PMC
January 2022

Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid.

Front Pharmacol 2021 24;12:795455. Epub 2021 Dec 24.

Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Given the important role of voltage-gated sodium (Na) channel-modulating spider toxins in elucidating the function, pharmacology, and mechanism of action of therapeutically relevant Na channels, we screened the venom from Australian theraphosid species against the human pain target hNa1.7. Using assay-guided fractionation, we isolated a 33-residue inhibitor cystine knot (ICK) peptide (Ssp1a) belonging to the NaSpTx1 family. Recombinant Ssp1a (rSsp1a) inhibited neuronal hNa subtypes with a rank order of potency hNa1.7 > 1.6 > 1.2 > 1.3 > 1.1. rSsp1a inhibited hNa1.7, hNa1.2 and hNa1.3 without significantly altering the voltage-dependence of activation, inactivation, or delay in recovery from inactivation. However, rSsp1a demonstrated voltage-dependent inhibition at hNa1.7 and rSsp1a-bound hNa1.7 opened at extreme depolarizations, suggesting rSsp1a likely interacted with voltage-sensing domain II (VSD II) of hNa1.7 to trap the channel in its resting state. Nuclear magnetic resonance spectroscopy revealed key structural features of Ssp1a, including an amphipathic surface with hydrophobic and charged patches shown by docking studies to comprise the interacting surface. This study provides the basis for future structure-function studies to guide the development of subtype selective inhibitors.
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http://dx.doi.org/10.3389/fphar.2021.795455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740163PMC
December 2021

Twenty-first century trends in the global epidemiology of pediatric-onset inflammatory bowel disease: systematic review.

Gastroenterology 2022 Jan 4. Epub 2022 Jan 4.

SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada; Child Health Evaluative Sciences, SickKids Research Institute, Toronto, Ontario, Canada; CHEO Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, CHEO, Ottawa, Ontario, Canada; CHEO Research Institute, Ottawa, Ontario, Canada; Department of Paediatrics and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: The incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed <21 years over the first two decades of the 21 century.

Methods: We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from 01/2010 to 02/2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn's disease (CD), ulcerative colitis (UC), and/or IBD-unclassified (IBDU). Data from studies published prior to 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD.

Results: 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31/37, 84%) studies reported significant increases in incidence and all (7/7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous.

Conclusions: Rates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported. However, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries.
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http://dx.doi.org/10.1053/j.gastro.2021.12.282DOI Listing
January 2022

Comparison of Prophylactic Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized Clinical Trial.

JAMA Oncol 2022 Jan 6. Epub 2022 Jan 6.

Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

Importance: The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited.

Objective: To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery.

Design, Setting, And Participants: This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility.

Interventions: A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen.

Main Outcomes And Measures: The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality.

Results: Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups.

Conclusions And Relevance: This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications.

Trial Registration: ClinicalTrials.gov Identifier: NCT01479283.
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http://dx.doi.org/10.1001/jamaoncol.2021.6628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739829PMC
January 2022

High-throughput and high-content bioassay enables tuning of polyester nanoparticles for cellular uptake, endosomal escape, and systemic in vivo delivery of mRNA.

Sci Adv 2022 Jan 5;8(1):eabk2855. Epub 2022 Jan 5.

Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abk2855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730632PMC
January 2022

Letter to the Editor: "Uterine Sarcoma Auto-amputation in an Infant with DICER1 Syndrome".

J Pediatr Adolesc Gynecol 2021 Dec 29. Epub 2021 Dec 29.

Departments of Pediatrics, Developmental Biology, Obstetrics & Gynecology and Surgery, Washington University School of Medicine, St. Louis, MO.

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http://dx.doi.org/10.1016/j.jpag.2021.12.012DOI Listing
December 2021

Waterbird solves the string-pull test.

R Soc Open Sci 2021 Dec 1;8(12):211343. Epub 2021 Dec 1.

Department of Psychology, Memorial University of Newfoundland, St John's, Canada.

String-pulling is among the most widespread cognitive tasks used to test problem-solving skills in mammals and birds. The task requires animals to comprehend that pulling on a non-valuable string moves an otherwise inaccessible food reward to within their reach. Although at least 90 avian species have been administered the string-pull test, all but five of them were perching birds (passeriformes) or parrots (psittaciformes). Waterbirds (Aequorlitornithes) are poorly represented in the cognitive literature, yet are known to engage in complex foraging behaviours. In this study, we tested whether free-living ring-billed gulls (), a species known for their behavioural flexibility and foraging innovativeness, could solve a horizontal string-pull test. Here, we show that 25% (26/104) of the ring-billed gulls that attempted to solve the test at least once over a maximum of three trials were successful, and that 21% of them (22/104) succeeded during their first attempt. Ring-billed gulls are thus the first waterbird known to solve a horizontal single-string-rewarded string-pull test. Since innovation rate and problem-solving are associated with species' ability to endure environmental alterations, we suggest that testing the problem-solving skills of other species facing environmental challenges will inform us of their vulnerability in a rapidly changing world.
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http://dx.doi.org/10.1098/rsos.211343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633784PMC
December 2021

Recognising and Treating Complicated Fissuring Perianal Crohn Disease: A South-East Scotland Cohort Study.

J Pediatr Gastroenterol Nutr 2022 Jan;74(1):68-71

Child Life and Health, University of Edinburgh.

Abstract: Fissuring perianal Crohn disease (CD) is not recognised as a perianal phenotype in Montreal/Paris inflammatory bowel disease classifications; however, can occasionally present as complicated disease with severe perianal pain driving increasingly intensive medical therapy despite well controlled luminal disease. We identified a regional cohort of prospectively acquired incident cases of paediatric CD diagnosed <16 years of age in South-East Scotland over a 19-year period (1999-2018), and conducted a retrospective review of complicated fissuring perianal CD causing severe pain related to anal sphincter complex spasm at defecation. Two hundred forty-seven new cases of paediatric CD were diagnosed with complicated fissuring perianal disease identified in 4 described cases (cumulative incidence 1.6%). These patients with marked fissuring and refractory anal sphincter complex spasm required neurostimulation-guided, 4-quadrant, anal intrasphincteric botulinum toxin (BT). All experienced immediate success, measured by cessation of spasms, with variable ongoing symptom relief after median (range) 3 (2-5) BT injections.
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http://dx.doi.org/10.1097/MPG.0000000000003285DOI Listing
January 2022

Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium.

Exp Eye Res 2021 Dec 17;215:108899. Epub 2021 Dec 17.

Department of Ophthalmology, University of Washington, Seattle, WA, 98109, USA. Electronic address:

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD), and a histologic hallmark of SFD is a thick layer of extracellular deposits beneath the retinal pigment epithelium (RPE). Previous studies of SFD patient-induced pluripotent stem cell (iPSC) derived RPE differ as to whether these cultures recapitulate this key clinical feature by forming increased drusenoid deposits. The primary purpose of this study is to examine whether SFD patient-derived iPSC-RPE form basal deposits similar to what is found in affected family member SFD globes and to determine whether SFD iPSC RPE may be more oxidatively stressed. We performed a careful comparison of iPSC RPE from three control individuals, multiple iPSC clones from two SFD patients' iPSC RPE, and post-mortem eyes of affected SFD family members. We also examined the effect of CRISPR-Cas9 gene correction of the S204C TIMP3 mutation on RPE phenotype. Finally, targeted metabolomics with liquid chromatography and mass spectrometry analysis and stable isotope-labeled metabolite analysis were performed to determine whether SFD RPE are more oxidatively stressed. We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks. These deposits were similar in composition to the thick layer of sub-RPE deposits found in SFD family member globes by immunofluorescence staining and TEM imaging. S204C TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits. We detected a ∼18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE, and targeted metabolomics showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE, suggesting increased ECM turnover. Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress. Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms.
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http://dx.doi.org/10.1016/j.exer.2021.108899DOI Listing
December 2021

Lumbar nerve root blocks using MRI - the effectiveness and safety of ultrasound/MRI fusion image guidance.

Br J Radiol 2022 Jan 7:20210599. Epub 2022 Jan 7.

Manor Hospital, Beach Road, Headington, Oxford, United Kingdom.

Objective: To compare the outcome of nerve root injection guided by ultrasound/MRI fusion with radiofrequency needle tracking (eTRAX) and the same procedure undertaken by fluoroscopic guidance.

Methods: This is a retrospective audit of anonymised clinical records from before and after a change in the imaging technique used to perform nerve root blocks.We studied 181 consecutive patients who had undergone a nerve root block, the first 124 guided by fluoroscopic technique and the next 57 guided by ultrasound/MRI fusion with radiofrequency needle guidance.Using pain diaries, we reviewed the outcome scores at 24 h and 2 weeks. We recorded the use of analgesia, the patient's satisfaction, complications and the duration of the procedures.

Results: Completed pain diaries were returned by 61% in the fluoroscopy group and 67% in the fusion imaging group.The visual analogue pain score was reduced at 24 h by 3.29 [standard deviation (SD) 2.35] for the fluoroscopy group and by 3.69 (SD 2.58) in the fusion group (p 0.399).At two weeks the pain reduction was 3.27 (SD 2.57) for the fluoroscopic group and 4.21 (SD 2.95) for the fusion group (p 0.083). There was no statistically significant difference between the groups.The patient's satisfaction scores were similar for both groups.The procedure by the two guidance methods took a similar time to perform.There were no serious complications in either group. One patient in the fusion-guided nerve root block group experienced paraesthesia in the nerve distribution for 2 h.

Conclusion: Ultrasound/MRI fusion imaging with needle tracking is an effective alternative to fluoroscopic image-guided injection.

Advances In Knowledge: Fusion imaging guidance provides the same outcome as fluoroscopic guidance.Fusion imaging guidance avoids the need for ionising radiation.
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http://dx.doi.org/10.1259/bjr.20210599DOI Listing
January 2022

Automated Segmentation of spinal Muscles from Upright Open MRI Using a Multi-Scale Pyramid 2D Convolutional Neural Network.

Spine (Phila Pa 1976) 2021 Dec 15. Epub 2021 Dec 15.

ICORD, Blusson Spinal Cord Centre, University of British Columbia, Vancouver, BC, Canada Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada Department of Mechanical Engineering, University of British Columbia, Vancouver, BC, Canada Electrical and Computer Engineering Department, University of British Columbia, Vancouver, BC, Canada Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada Centre for Hip Health and Mobility, University of British Columbia, Vancouver, Canada.

Study Design: Randomized trial.

Objective: To implement an algorithm enabling the automated segmentation of spinal muscles from open MR images in healthy volunteers and patients with adult spinal deformity (ASD).

Summary Of Background Data: Understanding spinal muscle anatomy is critical to diagnosing and treating spinal deformity. Muscle boundaries can be extrapolated from medical images using segmentation, which is usually done manually by clinical experts and remains complicated and time-consuming.

Methods: Three groups were examined: two healthy volunteer groups (N = 6 for each group) and one ASD group (N = 8 patients) were imaged at the lumbar and thoracic regions of the spine in an upright open MRI scanner while maintaining different postures (various seated, standing and supine). For each group and region, a selection of regions of interest (ROIs) were manually segmented. A multi-scale pyramid 2D convolutional neural network was implemented to automatically segment all defined ROIs. A five-fold cross-validation method was applied and distinct models were trained for each resulting set and group and evaluated using Dice coefficients calculated between the model output and the manually segmented target.

Results: Good to excellent results were found across all ROIs for the ASD (Dice coefficient > 0.76) and healthy (dice coefficient > 0.86) groups.

Conclusion: This study represents a fundamental step toward the development of an automated spinal muscle properties extraction pipeline, which will ultimately allow clinicians to have easier access to patient-specific simulations, diagnosis and treatment.Level of Evidence: 2.
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http://dx.doi.org/10.1097/BRS.0000000000004308DOI Listing
December 2021

Technology and Universal Health Coverage: Examining the role of digital health.

J Glob Health 2021 20;11:16006. Epub 2021 Nov 20.

The World Bank, Washington, DC, USA.

While there is tremendous promise to leverage technology for UHC, it will require smart, context-specific policies and programming with ample flexibility to adapt as needs and opportunities change - and with robust safeguards to protect privacy, data security, and equity. The health sector, by its very nature of being data intensive, lends itself to the use of technology for analytics to improve health outcomes, respond to public health crises, and efficiently and equitably allocate resources. The first imperative in considering the use of digital health to expand UHC is to remember that digital health is a means to an end, and only one of the available means. Efforts leveraging digital health to move along that path to universality have taken many forms: to increase the number of people reached, to provide enhanced service coverage, and to reduce the financial burdens on individuals in need of health care. Making use of digital health interventions is an evolving process, not a one-time decision point. It is context specific and needs a clear vision to move from pilot interventions to scaled implementation. Technology can be a key tool in achieving UHC but its use has to be strategic, judicious, and cognizant of issues around privacy and patient rights.
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http://dx.doi.org/10.7189/jogh.11.16006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645240PMC
December 2021

Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH).

Front Oncol 2021 19;11:778925. Epub 2021 Nov 19.

XPose Therapeutics, Inc., San Carlos, CA, United States.

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme's ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.
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http://dx.doi.org/10.3389/fonc.2021.778925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653755PMC
November 2021

Automatic Deep Learning Segmentation and Quantification of Epicardial Adipose Tissue in Non-Contrast Cardiac CT scans.

Annu Int Conf IEEE Eng Med Biol Soc 2021 11;2021:3938-3942

An Automatic deep learning semantic segmentation (ADLS) using DeepLab-v3-plus technique is proposed for a full and accurate whole heart Epicardial adipose tissue (EAT) segmentation from non-contrast cardiac CT scan. The ADLS algorithm was trained on manual segmented scans of the enclosed region of the pericardium (sac), which represents the internal heart tissues where the EAT is located. A level of 40 Hounsfield unit (HU) and a window of 350 HU was applied to every axial slice for contrast enhancement. Each slice was associated with two additional consecutive slices, representing the three-channel single input image of the deep network. The detected output mask region, as a post-step, was thresholded between [-190, -30] HU to detect the EAT region. A median filter with kernel size 3mm was applied to remove the noise. Using 70 CT scans (50 training/20 testing), the ADLS showed excellent results compared to manual segmentation (ground truth). The total average Dice score was (89.31%±1.96) with a high correlation of (R=97.15%, p-value <0.001), while the average error of EAT volume was (0.79±9.21).Clinical Relevance- Epicardial adipose tissue (EAT) volume aids in predicting atherosclerosis development and is linked to major adverse cardiac events. However, accurate manual segmentation is considered tedious work and requires skilled expertise.
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http://dx.doi.org/10.1109/EMBC46164.2021.9630953DOI Listing
November 2021

Ligation of Boratabenzene and 9-Borataphenanthrene to Coinage Metals.

Inorg Chem 2021 Dec 8;60(24):18981-18989. Epub 2021 Dec 8.

Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798, United States.

The reactions of boratabenzene and borataphenanthrene anions with group 11 PhPMCl reagents furnished η coordination complexes, with the exception of the copper boratabenzene species that adopted an η mode. The binding of arene ligands to copper in an η manner is rare, and altering the ancillary ligand on copper to an N-heterocyclic carbene switched the binding of the boratabenzene to η, indicating that such ligands are capable of vacating coordination sites. The η coordination complexes bind side-on, akin to olefins, via a borataalkene unit, although with the carbon atom much more proximal to the metal center than boron.
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http://dx.doi.org/10.1021/acs.inorgchem.1c02800DOI Listing
December 2021

Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses.

Angew Chem Int Ed Engl 2022 Feb 22;61(6):e202111829. Epub 2021 Dec 22.

Department of Chemistry, ChEM-H Institute, and Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.

Mitochondrial function in cells declines with aging and with neurodegeneration, due in large part to accumulated mutations in mitochondrial DNA (mtDNA) that arise from deficient DNA repair. However, measuring this repair activity is challenging. We employ a molecular approach for visualizing mitochondrial base excision repair (BER) activity in situ by use of a fluorescent probe (UBER) that reacts rapidly with AP sites resulting from BER activity. Administering the probe to cultured cells revealed signals that were localized to mitochondria, enabling selective observation of mtDNA BER intermediates. The probe showed elevated DNA repair activity under oxidative stress, and responded to suppression of glycosylase activity. Furthermore, the probe illuminated the time lag between the initiation of oxidative stress and the initial step of BER. Absence of MTH1 in cells resulted in elevated demand for BER activity upon extended oxidative stress, while the absence of OGG1 activity limited glycosylation capacity.
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http://dx.doi.org/10.1002/anie.202111829DOI Listing
February 2022

Using allocative efficiency analysis to inform health benefits package design for progressing towards Universal Health Coverage: Proof-of-concept studies in countries seeking decision support.

PLoS One 2021 29;16(11):e0260247. Epub 2021 Nov 29.

Bill & Melinda Gates Foundation, Seattle, Washington, United States of America.

Background: Countries are increasingly defining health benefits packages (HBPs) as a way of progressing towards Universal Health Coverage (UHC). Resources for health are commonly constrained, so it is imperative to allocate funds as efficiently as possible. We conducted allocative efficiency analyses using the Health Interventions Prioritization tool (HIPtool) to estimate the cost and impact of potential HBPs in three countries. These analyses explore the usefulness of allocative efficiency analysis and HIPtool in particular, in contributing to priority setting discussions.

Methods And Findings: HIPtool is an open-access and open-source allocative efficiency modelling tool. It is preloaded with publicly available data, including data on the 218 cost-effective interventions comprising the Essential UHC package identified in the 3rd Edition of Disease Control Priorities, and global burden of disease data from the Institute for Health Metrics and Evaluation. For these analyses, the data were adapted to the health systems of Armenia, Côte d'Ivoire and Zimbabwe. Local data replaced global data where possible. Optimized resource allocations were then estimated using the optimization algorithm. In Armenia, optimized spending on UHC interventions could avert 26% more disability-adjusted life years (DALYs), but even highly cost-effective interventions are not funded without an increase in the current health budget. In Côte d'Ivoire, surgical interventions, maternal and child health and health promotion interventions are scaled up under optimized spending with an estimated 22% increase in DALYs averted-mostly at the primary care level. In Zimbabwe, the estimated gain was even higher at 49% of additional DALYs averted through optimized spending.

Conclusions: HIPtool applications can assist discussions around spending prioritization, HBP design and primary health care transformation. The analyses provided actionable policy recommendations regarding spending allocations across specific delivery platforms, disease programs and interventions. Resource constraints exacerbated by the COVID-19 pandemic increase the need for formal planning of resource allocation to maximize health benefits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260247PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629222PMC
December 2021

Viral Phrenology.

Viruses 2021 10 30;13(11). Epub 2021 Oct 30.

Department of Physics, Kalamazoo College, Kalamazoo, MI 49006, USA.

We introduce Viral Phrenology, a new scheme for understanding the genomic composition of spherical viruses based on the locations of their structural protrusions. We used icosahedral point arrays to classify 135 distinct viral capsids collected from over 600 capsids available in the VIPERdb. Using gauge points of point arrays, we found 149 unique structural protrusions. We then show how to use the locations of these protrusions to determine the genetic composition of the virus. We then show that ssDNA, dsDNA, dsRNA and ssRNA viruses use different arrangements for distributing their protrusions. We also found that Triangulation number is also partially dependent on the structural protrusions. This analysis begins to tie together Baltimore Classification and Triangulation number using point arrays.
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http://dx.doi.org/10.3390/v13112191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618131PMC
October 2021

Open MRI assessment of anterior femoroacetabular clearance in active and passive impingement-provoking postures.

Bone Jt Open 2021 Nov;2(11):988-996

Center for Hip Health and Mobility, University of British Columbia, Vancouver, British Columbia, Canada.

Aims: Cam and pincer morphologies are potential precursors to hip osteoarthritis and important contributors to non-arthritic hip pain. However, only some hips with these pathomorphologies develop symptoms and joint degeneration, and it is not clear why. Anterior impingement between the femoral head-neck contour and acetabular rim in positions of hip flexion combined with rotation is a proposed pathomechanism in these hips, but this has not been studied in active postures. Our aim was to assess the anterior impingement pathomechanism in both active and passive postures with high hip flexion that are thought to provoke impingement.

Methods: We recruited nine participants with cam and/or pincer morphologies and with pain, 13 participants with cam and/or pincer morphologies and without pain, and 11 controls from a population-based cohort. We scanned hips in active squatting and passive sitting flexion, adduction, and internal rotation using open MRI and quantified anterior femoroacetabular clearance using the β angle.

Results: In squatting, we found significantly decreased anterior femoroacetabular clearance in painful hips with cam and/or pincer morphologies (mean -11.3° (SD 19.2°)) compared to pain-free hips with cam and/or pincer morphologies (mean 8.5° (SD 14.6°); p = 0.022) and controls (mean 18.6° (SD 8.5°); p < 0.001). In sitting flexion, adduction, and internal rotation, we found significantly decreased anterior clearance in both painful (mean -15.2° (SD 15.3°); p = 0.002) and painfree hips (mean -4.7° (SD 13°); p = 0.010) with cam and/pincer morphologies compared to the controls (mean 7.1° (SD 5.9°)).

Conclusion: Our results support the anterior femoroacetabular impingement pathomechanism in hips with cam and/or pincer morphologies and highlight the effect of posture on this pathomechanism. Cite this article:  2021;2(11):988-996.
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http://dx.doi.org/10.1302/2633-1462.211.BJO-2021-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636292PMC
November 2021

Cyclizations and fragmentations in the alkylation of 6-chloro-5-hydroxy-4-aminopyrimidines with aminoalkyl chlorides.

J Heterocycl Chem 2021 Apr 10;58(4):947-951. Epub 2021 Feb 10.

Chemistry, School of Natural and Environmental Sciences Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Newcastle University Newcastle upon Tyne UK.

Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biological activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. We describe a route to 4,6-diamino-5-alkoxypyrimidines via a SAr-alkylation-SAr sequence from readily available 4,6-dichloro-5-methoxypyrimidine, which allows the synthesis of such compounds with regiochemical control. The extension of this approach to alkylating agents bearing amino substituents led to unexpected and, in some cases, unprecedented products resulting from intramolecular SAr cyclization and subsequent fragmentation.
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http://dx.doi.org/10.1002/jhet.4228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600947PMC
April 2021

Open MRI validation of a hip model driven with subject-specific motion capture data in predicting anterior femoroacetabular clearance.

BMC Musculoskelet Disord 2021 Nov 23;22(1):972. Epub 2021 Nov 23.

Center for Hip Health and Mobility, University of British Columbia, Vancouver, BC, Canada.

Background: Cam and/or pincer morphologies (CPM) are potential precursors to hip osteoarthritis (OA) and important contributors to non-arthritic hip pain. However, only some CPM hips develop OA and/or pain, and it is not clear why. Anterior impingement between the femoral head/neck contour and acetabular rim during motion is a proposed pathomechanism. Understanding how activity and deformity combine to produce impingement may shed light on the causes of hip degeneration/pain. The objective of this study was to determine the accuracy of a subject-specific hip model driven by subject-specific motion data in predicting anterior impingement.

Methods: We recruited 22 participants with CPM (both with and without pain) and 11 controls. We collected subject-specific 3D kinematics during squatting and sitting flexion, adduction, and internal rotation (FADIR) (an active and a passive maneuver, respectively, proposed to provoke impingement). We then developed 3D subject-specific hip models from supine 3T hip MRI scans that predicted the beta angle (a measure of anterior femoroacetabular clearance) for each frame of acquired kinematics. To assess the accuracy of these predictions, we measured the beta angle directly in the final position of squatting and sitting FADIR using open MRI scans. We selected the frame of motion data matching the static imaged posture using the least-squares error in hip angles. Model accuracy for each subject was calculated as the absolute error between the open MRI measure of beta and the model prediction of beta at the matched time frame. To make the final model accuracy independent of goodness of match between open MRI position and motion data, a threshold was set for least-squares error in hip angles, and only participants that were below this threshold were considered in the final model accuracy calculation, yielding results from 10 participants for squatting and 7 participants for sitting FADIR.

Results: For squatting and sitting FADIR, we found an accuracy of 1.1°(0.8°) and 1.3°(mean (SD), and root mean squared error, respectively) and 0.5°(0.3°) and 0.6°, respectively.

Conclusion: This subject-specific hip model predicts anterior femoroacetabular clearance with an accuracy of about 1°, making it useful to predict anterior impingement during activities measured with motion analysis.
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http://dx.doi.org/10.1186/s12891-021-04820-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609822PMC
November 2021

Magnetic resonance molecular imaging of extradomain B fibronectin enables detection of pancreatic ductal adenocarcinoma metastasis.

Magn Reson Imaging 2022 Feb 19;86:37-45. Epub 2021 Nov 19.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States of America; Case Comprehensive Cancer Center, Case Western Reserve School of Medicine, Cleveland, OH 44106, United States of America. Electronic address:

Extradomain-B Fibronectin (EDB-FN) is an oncomarker that can be visualized with magnetic resonance molecular imaging (MRMI) to detect pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we sought to assess the expression of EDB-FN in clinical samples of PDAC and to evaluate MRMI of PDAC metastasis with an EDB-FN-specific gadolinium-based contrast agent (MT218) in an orthotopic KPC-GFP-Luc mouse model. EDB-FN expression was evaluated in PDAC tissue samples through immunohistochemistry. RNA-Seq data obtained from the GEPIA2 project was evaluated to demonstrate EDB-FN expression in large patient cohorts. FLASH-3D MRI at 3 T of the KPC-GFP-Luc metastasis model was performed following injection of MT218. Tumor enhancement in MR images was correlated to postmortem distribution of KPC-GFP-Luc tumors using fluorescent and bright-field cryo-imaging and anatomical landmarks. EDB-FN immunohistochemical staining scores of human metastatic tumor stroma, (2.17 ± 0.271), metastatic tumor parenchyma (2.08 ± 0.229), primary tumor stroma (1.61 ± 0.26), and primary tumor parenchyma (1.61 ± 0.12) were significantly (p < 0.0001) higher than normal pancreas stroma (0.14 ± 0.10) and normal pancreas parenchyma (0.14 ± 0.14). EDB-FN mRNA expression in tumors is 4.98 log(TPM + 1) and 0.18 log(TPM + 1) in normal tissue (p < 0.01). A mouse model of EDB-FN rich PDAC metastasis exhibited T-weighted contrast to noise (CNR) changes of 21.80 ± 4.34 in perimetastatic regions and 8.38 ± 0.79 in metastatic regions identified through cryo-imaging, significantly higher (p < 0.05) than CNR changes found in normal liver (-6.43 ± 0.92), mesentery (2.24 ± 0.92), spleen (-3.06 ± 2.38) and intestine (1.08 ± 2.15). We conclude that EDB-FN is overexpressed in metastatic and primary PDAC tumors and MRMI with MT218 enables the detection of metastatic and perimetastatic tissues.
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http://dx.doi.org/10.1016/j.mri.2021.11.008DOI Listing
February 2022
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