Publications by authors named "David Miller"

2,332 Publications

  • Page 1 of 1

Emergency department utilization among deaf and hard-of-hearing patients: A retrospective chart review.

Disabil Health J 2022 Apr 20:101327. Epub 2022 Apr 20.

Department of Health Education and Behavior, University of Florida, Gainesville, FL, USA. Electronic address:

Background: Deaf and hard-of-hearing (DHH) patients are an underserved priority population. Existing, although contextually limited, findings indicate that DHH patients are more likely to use the emergency department (ED) than non-DHH patients. However, little attention has been given to the differences in ED utilization by patients' language modalities.

Objective: We hypothesized that DHH ASL-users and DHH English speakers would have higher rates of ED utilization in the past 36 months than non-DHH English speakers.

Methods: We used a retrospective chart review design using data from a large academic medical center in the southeastern United States. In total, 277 DHH ASL-users, 1000 DHH English speakers, and 1000 non-DHH English speakers were included. We used logistic regression and zero-inflated modeling to assess relations between patient segment and ED utilization in the past 12- and 36-months. We describe primary ED visit diagnosis codes using AHRQ Clinical Classifications Software.

Results: DHH ASL users and DHH English speakers had higher adjusted odds ratios of using the ED in the past 36-months than non-DHH English speakers (aORs = 1.790 and 1.644, respectively). Both DHH ASL users and DHH English speakers had a higher frequency of ED visits among patients who used the ED in the past 36-months (61.0% and 70.1%, respectively). The most common principal diagnosis code was for abdominal pain, with DHH English speakers making up over half of all abdominal pain encounters.

Conclusions: DHH ASL users and DHH English speakers are at higher risk of using the ED compared to non-DHH English speakers. We call for additional attention on DHH patients in health services and ED utilization research.
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http://dx.doi.org/10.1016/j.dhjo.2022.101327DOI Listing
April 2022

Shipping in the north-east Atlantic: Identifying spatial and temporal patterns of change.

Mar Pollut Bull 2022 May 12;179:113681. Epub 2022 May 12.

Scotland's Rural College (SRUC), Craibstone Estate, Aberdeen, AB21 9YA Scotland, United Kingdom of Great Britain and Northern Ireland. Electronic address:

Maritime traffic is increasing globally, with a four-fold increase in commercial vessel movements between 1992 and 2012. Vessels contribute to noise and air pollution, provide pathways for non-native species, and collide with marine wildlife. While knowledge of shipping trends and potential environmental impacts exists at both local and global levels, key information on vessel density for regional-scale management is lacking. This study presents the first in-depth spatio-temporal analysis of shipping in the north-east Atlantic region, over three years in a five-year period. Densities increased by 34%, including in 73% of Marine Protected Areas. Western Scotland and the Bay of Biscay experienced the largest increases in vessel density, predominantly from small and slow vessels. Given well-documented impacts that shipping can have on the marine environment, it is crucial that this situation continues to be monitored - particularly in areas designated to protect vulnerable species and ecosystems which may already be under pressure.
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http://dx.doi.org/10.1016/j.marpolbul.2022.113681DOI Listing
May 2022

Early diagnosis of acute kidney injury subsequent to severe hypotension and fluid resuscitation in anaesthetized dogs.

Vet Anaesth Analg 2022 Mar 9. Epub 2022 Mar 9.

School of Veterinary Medicine, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, Western Australia, Australia.

Objectives: To document changes in urinary biomarker concentration and conventional diagnostic tests of acute kidney injury (AKI) following hypotension and fluid resuscitation in anaesthetized dogs.

Study Design: Experimental, repeated measures, prospective study.

Animals: A group of six male adult Greyhound dogs.

Methods: Following general anaesthesia, severe hypotension was induced by phlebotomy, maintaining mean arterial blood pressure (MAP) < 40 mmHg for 60 minutes, followed by resuscitation with intravenous gelatine solution to maintain MAP > 60 mmHg for 3 hours. Following euthanasia, renal tissue was examined by light microscopy (LM) and transmission electron microscopy (TEM). Urinary and serum concentrations of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC), and gamma-glutamyl transpeptidase (GGT), serum creatinine and urine output were measured at baseline and hourly until euthanasia. Data are presented as mean and 95% confidence interval and analysed using repeated measures analysis of variance with Dunnett's adjustment, p < 0.05.

Results: Structural damage to proximal renal tubular cells was evident on LM and TEM. Urinary biomarker concentrations were significantly elevated from baseline, peaking 2 hours after haemorrhage at 19.8 (15.1-25.9) ng mL NGAL (p = 0.002), 2.54 (1.64-3.43) mg mL CysC (p = 0.009) and 2043 (790-5458) U L GGT (p < 0.001). Serum creatinine remained within a breed-specific reference interval in all dogs. Urinary protein-creatinine ratio (UPC) was significantly elevated in all dogs from 1 hour following haemorrhage.

Conclusions And Clinical Relevance: Urinary NGAL, CysC and GGT concentrations, and UPC were consistently elevated within 1 hour of severe hypotension, suggesting that proximal renal tubules are damaged in the earliest stage of ischaemia-reperfusion AKI. Measurement of urinary biomarkers may allow early diagnosis of AKI in anaesthetized dogs. Urinary GGT concentration and UPC are particularly useful as they can be measured on standard biochemistry analysers.
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http://dx.doi.org/10.1016/j.vaa.2022.02.006DOI Listing
March 2022

Outcomes of Shared Decision-Making for Low-Dose Screening for Lung Cancer in an Academic Medical Center.

J Cancer Educ 2022 Apr 30. Epub 2022 Apr 30.

Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Shared decision-making (SDM) helps patients weigh risks and benefits of screening approaches. Little is known about SDM visits between patients and healthcare providers in the context of lung cancer screening. This study explored the extent that patients were informed by their provider of the benefits and harms of lung cancer screening and expressed certainty about their screening choice. We conducted a survey with 75 patients from an academic medical center in the Southeastern U.S. Survey items included knowledge of benefits and harms of screening, patients' value elicitation during SDM visits, and decisional certainty. Patient and provider characteristics were collected through electronic medical records or self-report. Descriptive statistics, Kruskal-Wallis tests, and Pearson correlations between screening knowledge, value elicitation, and decisional conflict were calculated. The sample was predominately non-Hispanic White (73.3%) with no more than high school education (53.4%) and referred by their primary care provider for screening (78.7%). Patients reported that providers almost always discussed benefits of screening (81.3%), but infrequently discussed potential harms (44.0%). On average, patients had low knowledge about screening (score = 3.71 out of 8) and benefits/harms. Decisional conflict was low (score = - 3.12) and weakly related to knowledge (R= - 0.25) or value elicitation (R= - 0.27). Black patients experienced higher decisional conflict than White patients (score = - 2.21 vs - 3.44). Despite knowledge scores being generally low, study patients experienced low decisional conflict regarding their decision to undergo lung cancer screening. Additional work is needed to optimize the quality and consistency of information presented to patients considering screening.
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http://dx.doi.org/10.1007/s13187-022-02148-wDOI Listing
April 2022

Over-regulation of aflatoxin M1 is expensive and harmful in food-insecure countries.

Authors:
J David Miller

Am J Clin Nutr 2022 Apr 25. Epub 2022 Apr 25.

Department of Chemistry, Carleton University, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1093/ajcn/nqac071DOI Listing
April 2022

Sperm selection with hyaluronic acid improved live birth outcomes among older couples and was connected to sperm DNA quality, potentially affecting all treatment outcomes.

Hum Reprod 2022 Apr 23. Epub 2022 Apr 23.

Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds, Leeds, UK.

Study Question: What effects did treatment using hyaluronic acid (HA) binding/selection prior to ICSI have on clinical outcomes in the Hyaluronic Acid Binding sperm Selection (HABSelect) clinical trial?

Summary Answer: Older women randomized to the trial's experimental arm (selection of sperm bound to immobilized (solid-state) HA) had the same live birth rates as younger women, most likely a result of better avoidance of sperm with damaged DNA.

What Is Known Already: Recent randomized controlled trials (RCTs) investigating the efficacy of HA-based sperm selection prior to ICSI, including HABSelect, have consistently reported reductions in the numbers of miscarriages among couples randomized to the intervention, suggesting a pathological sperm-mediated factor mitigated by prior HA-binding/selection. The mechanism of that protection is unknown.

Study Design, Size, Duration: The original HABSelect Phase 3 RCT ran from 2014 to 2017 and included 2752 couples from whom sperm samples used in control (ICSI) and intervention (Physiological IntraCytoplasmic Sperm Injection; PICSI) arms of the trial were stored frozen for later assessment of DNA quality (DNAq). The trial overlapped with its mechanistic arm, running from 2016 to 2018.

Participants/materials, Setting, Methods: As miscarriage reduction was a significant secondary outcome of the trial, samples (n = 1247) selected for the mechanistic analysis were deliberately enriched for miscarriage outcomes (n = 92 or 7.4%) from a total of 154 miscarriages (5.6%) among all (n = 2752) couples randomized by stratified random sampling. Values from fresh semen samples for sperm concentration (mml), percentage forward progressive motility and percentage HA-binding score (HBS) were obtained before being processed by differential density gradient centrifugation or (rarely) by swim-up on the day of treatment. Surplus sperm pellets were recovered, aliquoted and cryopreserved for later analysis of DNAq using slide-based Comet, TUNEL, acridine orange (AO) and the sperm chromatin dispersion (SCD) assays. Following their classification into normal and abnormal sample subcategories based on reference values for sperm concentration and motility, relationships with HBS and DNAq were examined by Spearman correlation, Student's t-tests, Mann Whitney U tests, and logistic regression (univariable and multivariable). Parsimonious selection enabled the development of models for exploring and explaining data trends. Potential differences in future cumulative pregnancy rates relating to embryo quality were also explored.

Main Results And The Role Of Chance: Results from the 1247 sperm samples assayed for HBS and/or DNAq, generated data that were considered in relation to standard physiological measures of (sperm) vitality and to treatment outcomes. All measures of HBS and DNAq discriminated normal from abnormal sperm samples (P < 0.001). SCD correlated negatively with the Comet (r = -0.165; P < 0.001) and TUNEL assays (r = -0.200; P < 0.001). HBS correlated negatively with AO (r = -0.211; P < 0.001), Comet (r = -0.127; P < 0.001) and TUNEL (r = -0.214; P < 0.001) and positively with SCD (r = 0.255; P < 0.001). A model for predicting live birth (and miscarriage) rates included treatment allocation (odds ratio: OR 2.167, 95% CI 1.084-4.464, P = 0.031), female age (OR 0.301, 95% CI 0.133-0.761, P = 0.013, per decade) and the AO assay (OR 0.79, 95% CI 0.60-1. 02.761, P = 0.073, per 10 points rise). A model predicting the expected rate of biochemical pregnancy included male age (OR 0.464, 95% CI 0.314-0.674, P < 0.001, per decade) and the SCD assay (OR 1.04, 95% CI 1.007-1.075, P = 0.018, per 10 point rise). A model for conversion from biochemical to clinical pregnancy did not retain any significant patient or assay variables. A model for post-injection fertilization rates included treatment allocation (OR 0.83, 95% CI 0.75-0.91, P < 0.001) and the Comet assay (OR 0.950, 95% CI 0.91-1.00, P = 0.041).

Limitations, Reasons For Caution: HABSelect was a prospective RCT and the mechanistic study group was drawn from its recruitment cohort for retrospective analysis, without the full benefit of randomization. The clinical and mechanistic aspects of the study were mutually exclusive in that measures of DNAq were obtained from residual samples and not from HA-selected versus unselected sperm. Models for fitting mechanistic with baseline and other clinical data were developed to compensate for variable DNAq data quality. HABSelect used a solid-state version of PICSI and we did not assess the efficacy of any liquid-state alternatives. PICSI reduced fertilization rates and did not improve the outlook for cumulative pregnancy rates.

Wider Implications Of The Findings: Notwithstanding the interventional effect on fertilization rates and possibly blastocyst formation (neither of which influenced pregnancy rates), poor sperm DNAq, reflected by lower HBS, probably contributed to the depression of all gestational outcomes including live births, in the HABSelect trial. The interventional avoidance of defective sperm is the best explanation for the equalization in live birth rates among older couples randomized to the trial's PICSI arm. As patients going forward for assisted conception cycles globally in future are likely to be dominated by an older demographic, HA-based selection of sperm for ICSI could be considered as part of their treatment plan.

Study Funding/competing Interest(s): The study was supported by the National Institute for Health Research (NIHR) EME (Efficacy and Mechanism Evaluation)-11-14-34. National Research Ethics Service approval 11/06/2013: 13/YH/0162. S.L. is CEO of ExamenLab Ltd (company number NI605309).

Trial Registration Number: ISRCTN99214271.
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http://dx.doi.org/10.1093/humrep/deac058DOI Listing
April 2022

Hyperactivation is sufficient to release porcine sperm from immobilized oviduct glycans.

Sci Rep 2022 Apr 19;12(1):6446. Epub 2022 Apr 19.

Department of Animal Sciences and Institute of Genomic Biology, University of Illinois at Urbana-Champaign, 1207 West Gregory Drive, Urbana, IL, 61801, USA.

Fertilizing sperm are retained by adhesion to specific glycans on the epithelium of the oviduct forming a reservoir before sperm are released from the reservoir so fertilization can ensue. Capacitated sperm lose affinity for the oviduct epithelium but the components of capacitation that are important for sperm release are uncertain. One important correlate of capacitation is the development of hyperactivated motility. Hyperactivation is characterized by asymmetrical flagellar beating with high beat amplitude. We tested whether the development of full-type asymmetrical motility was sufficient to release sperm from immobilized oviduct glycans. Sperm hyperactivation was induced by four different compounds, a cell-permeable cAMP analog (cBiMPS), CatSper activators (4-aminopyridine and procaine), and an endogenous steroid (progesterone). Using standard analysis (CASA) and direct visualization with high-speed video microscopy, we first confirmed that all four compounds induced hyperactivation. Subsequently, sperm were allowed to bind to immobilized oviduct glycans, and compounds or vehicle controls were added. All compounds caused sperm release from immobilized glycans, demonstrating that hyperactivation was sufficient to release sperm from oviduct cells and immobilized glycans. Pharmacological inhibition of the non-genomic progesterone receptor and CatSper diminished sperm release from oviduct glycans. Inhibition of the proteolytic activities of the ubiquitin-proteasome system (UPS), implicated in the regulation of sperm capacitation, diminished sperm release in response to all hyperactivation inducers. In summary, induction of sperm hyperactivation was sufficient to induce sperm release from immobilized oviduct glycans and release was dependent on CatSper and the UPS.
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http://dx.doi.org/10.1038/s41598-022-10390-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019019PMC
April 2022

Synthetic Negative Controls: Using Simulation to Screen Large-Scale Propensity Score Analyses.

Epidemiology 2022 Apr 12. Epub 2022 Apr 12.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

The propensity score has become a standard tool to control for large numbers of variables in healthcare database studies. However, little has been written on the challenge of comparing large-scale propensity score analyses that use different methods for confounder selection and adjustment. In these settings, balance diagnostics are useful but do not inform researchers on which variables balance should be assessed or quantify the impact of residual covariate imbalance on bias. Here, we propose a framework to supplement balance diagnostics when comparing large-scale propensity score analyses. Instead of focusing on results from any single analysis, we suggest conducting and reporting results for many analytic choices and using both balance diagnostics and synthetically generated control studies to screen analyses that show signals of bias caused by measured confounding. To generate synthetic datasets, the framework does not require simulating the outcome-generating process. In healthcare database studies, outcome events are often rare, making it difficult to identify and model all predictors of the outcome to simulate a confounding structure closely resembling the given study. Therefore, the framework uses a model for treatment assignment to divide the comparator population into pseudo-treatment groups where covariate differences resemble those in the study cohort. The partially simulated datasets have a confounding structure approximating the study population under the null (synthetic negative control studies). The framework is used to screen analyses that likely violate partial exchangeability due to lack of control for measured confounding. We illustrate the framework using simulations and an empirical example.
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http://dx.doi.org/10.1097/EDE.0000000000001482DOI Listing
April 2022

Broadband Solenoidal Haloscope for Terahertz Axion Detection.

Phys Rev Lett 2022 Apr;128(13):131801

Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

We introduce the Broadband Reflector Experiment for Axion Detection (BREAD) conceptual design and science program. This haloscope plans to search for bosonic dark matter across the [10^{-3},1]  eV ([0.24, 240] THz) mass range. BREAD proposes a cylindrical metal barrel to convert dark matter into photons, which a novel parabolic reflector design focuses onto a photosensor. This unique geometry enables enclosure in standard cryostats and high-field solenoids, overcoming limitations of current dish antennas. A pilot 0.7  m^{2} barrel experiment planned at Fermilab is projected to surpass existing dark photon coupling constraints by over a decade with one-day runtime. Axion sensitivity requires <10^{-20}  W/sqrt[Hz] sensor noise equivalent power with a 10 T solenoid and 10  m^{2} barrel. We project BREAD sensitivity for various sensor technologies and discuss future prospects.
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http://dx.doi.org/10.1103/PhysRevLett.128.131801DOI Listing
April 2022

Combining chemistry and protein engineering for new-to-nature biocatalysis.

Nat Synth 2022 Jan 12;1(1):18-23. Epub 2022 Jan 12.

Division of Chemistry and Chemical Engineering, California Institute of Technology Pasadena, California, 91125.

Biocatalysis, the application of enzymes to solve synthetic problems of human import, has blossomed into a powerful technology for chemical innovation. In the past decade, a threefold partnership, where nature provides blueprints for enzymatic catalysis, chemists introduce innovative activity modes with abiological substrates, and protein engineers develop new tools and algorithms to tune and improve enzymatic function, has unveiled the frontier of enzyme catalysis. In this perspective, we highlight examples of interdisciplinary studies which have helped to expand the scope of biocatalysis, including concepts of enzymatic versatility explored through the lens of biomimicry, to achieve both activities and selectivities that are not currently possible with chemocatalysis. We indicate how modern tools, such as directed evolution, computational protein design and machine learning-based protein engineering methods, have already impacted and will continue to influence enzyme engineering for new abiological transformations. A sustained collaborative effort across disciplines is anticipated to spur further advances in biocatalysis in the coming years.
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http://dx.doi.org/10.1038/s44160-021-00008-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995090PMC
January 2022

Controlled assembly of retinal cells on fractal and Euclidean electrodes.

PLoS One 2022 6;17(4):e0265685. Epub 2022 Apr 6.

Physics Department, University of Oregon, Eugene, Oregon, United States of America.

Controlled assembly of retinal cells on artificial surfaces is important for fundamental cell research and medical applications. We investigate fractal electrodes with branches of vertically-aligned carbon nanotubes and silicon dioxide gaps between the branches that form repeating patterns spanning from micro- to milli-meters, along with single-scaled Euclidean electrodes. Fluorescence and electron microscopy show neurons adhere in large numbers to branches while glial cells cover the gaps. This ensures neurons will be close to the electrodes' stimulating electric fields in applications. Furthermore, glia won't hinder neuron-branch interactions but will be sufficiently close for neurons to benefit from the glia's life-supporting functions. This cell 'herding' is adjusted using the fractal electrode's dimension and number of repeating levels. We explain how this tuning facilitates substantial glial coverage in the gaps which fuels neural networks with small-world structural characteristics. The large branch-gap interface then allows these networks to connect to the neuron-rich branches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985931PMC
April 2022

The experiences of community organizations partnering with a medical school to improve students' understanding of the social determinants of health: A qualitative study.

Med Teach 2022 Apr 6:1-8. Epub 2022 Apr 6.

Department of Internal Medicine and Implementation Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Purpose: There has been increasing interest among national organizations for medical schools to provide students experiential training in the social determinants of health (SDH) through community partnerships. Despite this interest, there is limited data about how these experiential activities can be designed most effectively, and community organizations' views of partnering with medical schools on these curricula is unknown. The authors' objective was to determine community organizations' and clinical clerkship directors' perceptions of the benefits and challenges of utilizing academic-community partnerships to improve medical students' understanding of the SDH.

Methods: The authors conducted a qualitative study consisting of open-ended, semi-structured interviews (between 2018 and 2021). All community organizations and clinical clerkship directors who partnered with a health equity curriculum were eligible to participate. Semi-structured interviews elicited participants' perceptions of the academic-community partnership; experience with the curriculum and the students; and recommendations for improving the curriculum. All interviews were audio recorded and transcribed. The authors used a directed content analysis approach to code the interviews inductively and identified emerging themes through an iterative process.

Results: Of the fifteen participants interviewed, ten were from community organizations and five from clinical clerkships. Three primary themes emerged: (1) community organizations felt educating students about the SDH aligned with the organization's mission and they benefited from consistent access to volunteers; (2) students benefited through greater exposure to the SDH; (3) participants suggested standardizing students' experiences, ensuring the students and organizations are clear about the goals and expectations, and working with organizations that have experience with or the capacity for a large volume of volunteers as ways to improve the experiential activity.

Conclusion: This study found that community organizations were very willing to partner with a medical school to provide students experiential learning about the SDH, and this partnership was beneficial for both the students and the organizations.
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http://dx.doi.org/10.1080/0142159X.2022.2056007DOI Listing
April 2022

BodyMapR: an R package and Shiny application designed to generate anatomical visualizations of cancer lesions.

JAMIA Open 2022 Apr 4;5(1):ooac013. Epub 2022 Mar 4.

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objectives: Structured real-world data (RWD), such as those found in cancer registries, provide a rich source of information regarding the natural history of cancer. Interactive data visualizations of cancer lesions can provide insights into certain clinical tumor characteristics (CTC). Software that can be integrated into an oncological data collection effort and generate anatomical data visualizations of CTC are limited.

Materials And Methods: We created BodyMapR: an R package and Shiny application that generates anatomical visualizations of cancer lesions from structured data.

Results: BodyMapR is a Shiny application that transposes structured data from REDCap onto an anatomical map to yield an interactive data visualization.

Conclusions: BodyMapR is freely available under the MIT license and can be obtained from GitHub. BodyMapR is executed in R and deployed as a Shiny application. It can be integrated into an existing cancer research platform and produces an interactive data visualization of CTC.
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http://dx.doi.org/10.1093/jamiaopen/ooac013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903180PMC
April 2022

Continuous blood flow visualization with laser speckle contrast imaging during neurovascular surgery.

Neurophotonics 2022 Apr 7;9(2):021908. Epub 2022 Mar 7.

The University of Texas at Austin, Department of Biomedical Engineering, Austin, Texas, United States.

Laser speckle contrast imaging (LSCI) has emerged as a promising tool for intraoperative cerebral blood flow (CBF) monitoring because it produces real-time full-field blood flow maps noninvasively and label free. We aim to demonstrate the ability of LSCI to continuously visualize blood flow during neurovascular procedures. LSCI hardware was attached to the surgical microscope and did not interfere with the normal operation of the microscope. To more easily visualize CBF in real time, LSCI images were registered with the built-in microscope white light camera such that LSCI images were overlaid on the white light images and displayed to the neurosurgeon continuously in real time. LSCI was performed throughout each surgery when the microscope was positioned over the patient, providing the surgeon with real-time visualization of blood flow changes before, during, and after aneurysm clipping or arteriovenous malformation (AVM) resection in humans. LSCI was also compared with indocyanine green angiography (ICGA) to assess CBF during aneurysm clipping and AVM surgery; integration of the LSCI hardware with the microscope enabled simultaneous acquisition of LSCI and ICGA. The results suggest that LSCI can provide continuous and real-time CBF visualization without affecting the surgeon workflow or requiring a contrast agent. The results also demonstrate that LSCI and ICGA provide different, yet complementary information about vessel perfusion.
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http://dx.doi.org/10.1117/1.NPh.9.2.021908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900813PMC
April 2022

Universal Screening in Primary Care Practices by Self-administered Tablet vs Nursing Staff.

JAMA Netw Open 2022 03 1;5(3):e221480. Epub 2022 Mar 1.

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina.

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http://dx.doi.org/10.1001/jamanetworkopen.2022.1480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905387PMC
March 2022

Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement.

J Am Chem Soc 2022 Mar 8;144(11):4739-4745. Epub 2022 Mar 8.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered "carbene transferase" enzymes. A laboratory-evolved variant of cytochrome P450, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.
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http://dx.doi.org/10.1021/jacs.2c00251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022672PMC
March 2022

Long-term retinal protection by MEK inhibition in Pax6 haploinsufficiency mice.

Exp Eye Res 2022 05 1;218:109012. Epub 2022 Mar 1.

Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Psychology, University of Virginia, Charlottesville, VA, USA; Program in Fundamental Neuroscience, University of Virginia, Charlottesville, VA, USA. Electronic address:

Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6 exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6 mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6 eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6 retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects.
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http://dx.doi.org/10.1016/j.exer.2022.109012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050935PMC
May 2022

Urbanization comprehensively impairs biological rhythms in coral holobionts.

Glob Chang Biol 2022 05 16;28(10):3349-3364. Epub 2022 Mar 16.

Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.

Coral reefs are in global decline due to climate change and anthropogenic influences (Hughes et al., Conservation Biology, 27: 261-269, 2013). Near coastal cities or other densely populated areas, coral reefs face a range of additional challenges. While considerable progress has been made in understanding coral responses to acute individual stressors (Dominoni et al., Nature Ecology & Evolution, 4: 502-511, 2020), the impacts of chronic exposure to varying combinations of sensory pollutants are largely unknown. To investigate the impacts of urban proximity on corals, we conducted a year-long in-natura study-incorporating sampling at diel, monthly, and seasonal time points-in which we compared corals from an urban area to corals from a proximal non-urban area. Here we reveal that despite appearing relatively healthy, natural biorhythms and environmental sensory systems were extensively disturbed in corals from the urban environment. Transcriptomic data indicated poor symbiont performance, disturbance to gametogenic cycles, and loss or shifted seasonality of vital biological processes. Altered seasonality patterns were also observed in the microbiomes of the urban coral population, signifying the impact of urbanization on the holobiont, rather than the coral host alone. These results should raise alarm regarding the largely unknown long-term impacts of sensory pollution on the resilience and survival of coral reefs close to coastal communities.
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http://dx.doi.org/10.1111/gcb.16144DOI Listing
May 2022

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Toxicol Appl Pharmacol 2022 04 15;440:115922. Epub 2022 Feb 15.

U.S. Environmental Protection Agency, Office of Pesticide Programs, Durham, NC, USA. Electronic address:

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.
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http://dx.doi.org/10.1016/j.taap.2022.115922DOI Listing
April 2022

Generalizable EHR-R-REDCap pipeline for a national multi-institutional rare tumor patient registry.

JAMIA Open 2022 Apr 7;5(1):ooab118. Epub 2022 Jan 7.

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: To develop a clinical informatics pipeline designed to capture large-scale structured Electronic Health Record (EHR) data for a national patient registry.

Materials And Methods: The EHR-R-REDCap pipeline is implemented using R statistical software to remap and import structured EHR data into the Research Electronic Data Capture (REDCap)-based multi-institutional Merkel Cell Carcinoma (MCC) Patient Registry using an adaptable data dictionary.

Results: Clinical laboratory data were extracted from EPIC Clarity across several participating institutions. Laboratory values (Labs) were transformed, remapped, and imported into the MCC registry using the EHR labs abstraction (eLAB) pipeline. Forty-nine clinical tests encompassing 482 450 results were imported into the registry for 1109 enrolled MCC patients. Data-quality assessment revealed highly accurate, valid labs. Univariate modeling was performed for labs at baseline on overall survival ( = 176) using this clinical informatics pipeline.

Conclusion: We demonstrate feasibility of the facile eLAB workflow. EHR data are successfully transformed and bulk-loaded/imported into a REDCap-based national registry to execute real-world data analysis and interoperability.
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http://dx.doi.org/10.1093/jamiaopen/ooab118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827011PMC
April 2022

Frequency and Symptoms of Intravitreal Silicone Oil Droplets Following Becton Dickinson and Norm-Ject Bevacizumab Injections.

Ophthalmic Surg Lasers Imaging Retina 2022 02 1;53(2):108-112. Epub 2022 Feb 1.

Background And Objective: To determine silicone oil droplet frequency and symptomatic impact in patients injected with Norm-Ject (NJ) and/or Becton Dickinson (BD) intravitreal bevacizumab.

Patients And Methods: This was a retrospective cohort study of 426 patients with prior bevacizumab injection(s). Symptomatic floaters questionnaire responses were compiled and statistical analysis was performed using Fisher's exact t test with 95% CI calculated via the modified Wald method.

Results: Patients who received BD intravitreal bevacizumab showed more droplets (67.2%) than those who received NJ intravitreal bevacizumab (7.8%), and droplets increased with injection quantity. However, the symptomatic patients reporting new floaters were similar (NJ: 39.22%, BD: 39.47%). .
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http://dx.doi.org/10.3928/23258160-20220124-03DOI Listing
February 2022

Geographic variation and thermal plasticity shape salamander metabolic rates under current and future climates.

Ecol Evol 2022 Jan 15;12(1):e8433. Epub 2022 Jan 15.

US Geological Survey Patuxent Wildlife Research Center SO Conte Anadromous Fish Research Lab Turners Falls Massachusetts USA.

Predicted changes in global temperature are expected to increase extinction risk for ectotherms, primarily through increased metabolic rates. Higher metabolic rates generate increased maintenance energy costs which are a major component of energy budgets. Organisms often employ plastic or evolutionary (e.g., local adaptation) mechanisms to optimize metabolic rate with respect to their environment. We examined relationships between temperature and standard metabolic rate across four populations of a widespread amphibian species to determine if populations vary in metabolic response and if their metabolic rates are plastic to seasonal thermal cues. Populations from warmer climates lowered metabolic rates when acclimating to summer temperatures as compared to spring temperatures. This may act as an energy saving mechanism during the warmest time of the year. No such plasticity was evident in populations from cooler climates. Both juvenile and adult salamanders exhibited metabolic plasticity. Although some populations responded to historic climate thermal cues, no populations showed plastic metabolic rate responses to future climate temperatures, indicating there are constraints on plastic responses. We postulate that impacts of warming will likely impact the energy budgets of salamanders, potentially affecting key demographic rates, such as individual growth and investment in reproduction.
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http://dx.doi.org/10.1002/ece3.8433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809431PMC
January 2022

Clinical utility of cell-free DNA liquid biopsies in Merkel cell carcinoma.

Dermatol Online J 2021 Oct 15;27(10). Epub 2021 Oct 15.

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.5070/D3271055629DOI Listing
October 2021

Evaluation of clinical characteristics and pre-biopsy impressions of primary Merkel cell carcinoma of the skin.

Dermatol Online J 2021 Oct 15;27(10). Epub 2021 Oct 15.

Harvard Medical School, Boston, Massachusetts, USA.

Merkel cell carcinoma is an aggressive carcinoma of the skin notable for protean presentation on physical exam. A retrospective cohort of 232 patients with primary cutaneous Merkel cell carcinoma was reviewed for availability of data on pre-biopsy clinical differential diagnosis based on clinical exam. Data was available for 192 patients (83%). The three most common impressions were cyst (33.3%), basal cell carcinoma (31.8%), and squamous cell carcinoma (19.8%). Merkel cell carcinoma was correctly suspected in only 13 cases (6.8%). A greater proportion of lesions that were less than or equal to 2 cm in diameter (10.2%) or carried BCC as a co-diagnosis (11.5%) were correctly suspected as Merkel cell carcinoma prior to biopsy, versus lesions greater than 2 cm in diameter (1.6%) or carrying SCC as a co-diagnosis (2.6%), suggesting that clinicians may be anchoring on the well-publicized concept of Merkel cell carcinoma as a small, pearly papule in real-world practice.
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http://dx.doi.org/10.5070/D3271055614DOI Listing
October 2021

Immunotherapy for Nonmelanoma skin cancer: Facts and Hopes.

Clin Cancer Res 2022 Feb 4. Epub 2022 Feb 4.

Medicine, Massachusetts General Hospital

Non-melanoma skin cancer (NMSC) is the most frequently diagnosed malignancy in humans, representing a broad range of cutaneous tumors. Keratinocyte carcinomas, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC), are the most common NMSCs. The incidence of BCC and CSCC are steadily increasing due to a progressively aging population, chronic exposure to ultraviolet radiation, and increased awareness with earlier diagnosis. Rarer NMSCs such as Merkel cell carcinoma (MCC) and cutaneous adnexal carcinomas (CACs) are also on the rise. Although the majority of NMSC tumors are localized at diagnosis and managed effectively with curative surgery and radiation, in rare cases with nodal and distant metastases, systemic therapy is often required. As our understanding of the immunologic characteristics of NMSCs has improved, effective treatment options have expanded with the development of immunotherapy. The U.S. Food and Drug Administration (FDA) recently approved several immune checkpoint inhibitors for the treatment of locally advanced and metastatic MCC, CSCC, and BCC. We review the emerging role of immunotherapy as the standard of care for several advanced NMSCs not amenable to surgery and/or radiation and underscore the need for considering clinical trials of novel strategies in patients when immunotherapy does not provide durable benefit. Finally, we explore the potential of neoadjuvant and adjuvant immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2971DOI Listing
February 2022

Design, Implementation, Utilization, and Sustainability of a Fast Healthcare Interoperability Resources-Based Inpatient Rounding List.

Appl Clin Inform 2022 01 2;13(1):180-188. Epub 2022 Feb 2.

Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States.

Objective: We designed and implemented an application programming interface (API)-based electronic health record (EHR)-integrated rounding list and evaluated acceptability, clinician satisfaction, information accuracy, and efficiency related to the application.

Methods: We developed and integrated an application, employing iterative design techniques with user feedback. EHR and application user action logs, as well as hospital safety reports, were evaluated. Rounding preparation characteristics were obtained through surveys before and after application integration. To evaluate usability, inpatient providers, including residents, fellows, and attendings were surveyed 2 weeks prior to and 6 months after enterprise-wide EHR application integration. Our primary outcome was provider time savings measured by user action logs; secondary outcomes include provider satisfaction.

Results: The application was widely adopted by inpatient providers, with more than 69% of all inpatients queried by the application within 6 months of deployment. Application utilization was sustained throughout the study period with 79% (interquartile range [IQR]: 76, 82) of enterprise-wide unique patients accessed per weekday. EHR action logs showed application users spent -3.24 minutes per day (95% confidence interval [CI]: -6.8, 0.33),  = 0.07 within the EHR compared with nonusers. Median self-reported chart review time for attendings decreased from 30 minutes (IQR: 15, 60) to 20 minutes (IQR: 10, 45) after application integration ( = 0.04). Self-reported sign-out preparation time decreased by a median of 5 minutes ( < 0.01), and providers were better prepared for hand-offs ( = 0.02). There were no increased safety reports during the study period.

Conclusion: This study demonstrates successful integration of a rounding application within a commercial EHR using APIs. We demonstrate increasing both provider-reported satisfaction and time savings. Rounding lists provided more accurate and timely information for rounds. Application usage was sustained across multiple specialties at 42 months. Other application designers should consider data density, optimization of provider workflows, and using real-time data transfer using novel tools when designing an application.
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http://dx.doi.org/10.1055/s-0041-1742219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810271PMC
January 2022

High-speed balanced-detection visible-light optical coherence tomography in the human retina using subpixel spectrometer calibration.

IEEE Trans Med Imaging 2022 Jan 28;PP. Epub 2022 Jan 28.

Increases in speed and sensitivity enabled rapid clinical adoption of optical coherence tomography (OCT) in ophthalmology. Recently, visible-light OCT (vis-OCT) achieved ultrahigh axial resolution, improved tissue contrast, and provided new functional imaging capabilities, demonstrating the potential to improve clinical care further. However, limited speed and sensitivity caused by the high relative intensity noise (RIN) in supercontinuum lasers impeded the clinical adoption of vis-OCT. To overcome these limitations, we developed balanced-detection vis-OCT (BD-vis-OCT), which uses two calibrated spectrometers to cancel RIN and other noises. We analyzed the RIN to achieve robust subpixel calibration between the two spectrometers and showed that BD-vis-OCT reduced the A-line noise floor by up to 20.5 dB. Metrics comparing signal-to-noise-ratios showed similar image qualities across multiple reference arm powers, a hallmark of operation near the shot-noise limit. We imaged healthy human retinas at an A-line rate of 125 kHz and a field-of-view up to 10 mm × 4 mm. We found that BD-vis-OCT revealed retinal anatomical features previously obscured by the noise floor.
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http://dx.doi.org/10.1109/TMI.2022.3147497DOI Listing
January 2022

The Role of DNA Methylation in Genome Defense in Cnidaria and Other Invertebrates.

Mol Biol Evol 2022 02;39(2)

ARC Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, QLD, Australia.

Considerable attention has recently been focused on the potential involvement of DNA methylation in regulating gene expression in cnidarians. Much of this work has been centered on corals, in the context of changes in methylation perhaps facilitating adaptation to higher seawater temperatures and other stressful conditions. Although first proposed more than 30 years ago, the possibility that DNA methylation systems function in protecting animal genomes against the harmful effects of transposon activity has largely been ignored since that time. Here, we show that transposons are specifically targeted by the DNA methylation system in cnidarians, and that the youngest transposons (i.e., those most likely to be active) are most highly methylated. Transposons in longer and highly active genes were preferentially methylated and, as transposons aged, methylation levels declined, reducing the potentially harmful side effects of CpG methylation. In Cnidaria and a range of other invertebrates, correlation between the overall extent of methylation and transposon content was strongly supported. Present transposon burden is the dominant factor in determining overall level of genomic methylation in a range of animals that diverged in or before the early Cambrian, suggesting that genome defense represents the ancestral role of CpG methylation.
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http://dx.doi.org/10.1093/molbev/msac018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857917PMC
February 2022

Over a decade of field physiology reveals life-history specific strategies to drought in garter snakes ().

Proc Biol Sci 2022 01 26;289(1967):20212187. Epub 2022 Jan 26.

Department of Ecology, Evolution, and Organismal Biology, Iowa State University, 2200 Osborn Drive, 251 Bessey Hall, Ames, IA 50011, USA.

Changing climates and severe weather events can affect population viability. Individuals need to buffer such negative fitness consequences through physiological plasticity. Whether certain life-history strategies are more conducive to surviving changing climates is unknown, but theory predicts that strategies prioritizing maintenance and survival over current reproduction should be better able to withstand such change. We tested this hypothesis in a meta-population of garter snakes having naturally occurring variation in life-history strategies. We tested whether slow pace-of-life (POL) animals, that prioritize survival over reproduction, are more resilient than fast POL animals as measured by several physiological biomarkers. From 2006 to 2019, which included two multi-year droughts, baseline and stress-induced reactivity of plasma corticosterone and glucose varied annually with directionalities consistent with life-history theory. Slow POL animals exhibited higher baseline corticosterone and lower baseline glucose, relative to fast POL animals. These patterns were also observed in stress-induced measures; thus, reactivity was equivalent between ecotypes. However, in drought years, measures of corticosterone did not differ between different life histories. Immune cell distribution showed annual variation independent of drought or life history. These persistent physiological patterns form a backdrop to several extirpations of fast POL populations, suggesting a limited physiological toolkit to surviving periods of extreme drought.
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http://dx.doi.org/10.1098/rspb.2021.2187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790353PMC
January 2022
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