Publications by authors named "M Craig Miller"

13,646 Publications

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Subgenomic flavivirus RNA (sfRNA) associated with Asian lineage Zika virus identified in three species of Ugandan bats (family Pteropodidae).

Sci Rep 2021 Apr 16;11(1):8370. Epub 2021 Apr 16.

Colorado State University, Fort Collins, CO, USA.

Serological cross-reactivity among flaviviruses makes determining the prior arbovirus exposure of animals challenging in areas where multiple flavivirus strains are circulating. We hypothesized that prior infection with ZIKV could be confirmed through the presence of subgenomic flavivirus RNA (sfRNA) of the 3' untranslated region (UTR), which persists in tissues due to XRN-1 stalling during RNA decay. We amplified ZIKV sfRNA but not NS5 from three experimentally-infected Jamaican fruit bats, supporting the hypothesis of sfRNA tissue persistence. Applying this approach to 198 field samples from Uganda, we confirmed presence of ZIKV sfRNA, but not NS5, in four bats representing three species: Eidolon helvum (n = 2), Epomophorus labiatus (n = 1), and Rousettus aegyptiacus (n = 1). Amplified sequence was most closely related to Asian lineage ZIKV. Our results support the use of sfRNA as a means of identifying previous flavivirus infection and describe the first detection of ZIKV RNA in East African bats.
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http://dx.doi.org/10.1038/s41598-021-87816-5DOI Listing
April 2021

Reduction in TLco and survival in a clinical population.

Eur Respir J 2021 Apr 16. Epub 2021 Apr 16.

Lung Function & Sleep, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

How best to express the level of lung gas transfer (TLco) function has not been properly explored. We used the most recent clinical data from 13 829 patients (54% male, 10% non-European ancestry), median age 60.5 years (range 20-97), median survival 3.5 years (range 0-20) to determine how best to express TLco function in terms of its relation to survival. The proportion of subjects of non-European ancestry with Global Lung Function Initiative (GLI) TLco z-scores above predicted was reduced but was significantly increased between -1.5 to -3.5 suggesting the need for ethnicity appropriate equations. Applying GLI FVC ethnicity methodology to GLI TLco z-scores removed this ethnic bias and was used for all subsequent analysis. TLco z-scores using the GLI equations were compared with Miller's US equations with median TLco z-scores being -1.43 and -1.50 for GLI and Miller equations respectively (interquartile range -2.8 to -0.3 and -2.4 to -0.7, respectively). GLI TLco z-scores gave the best Cox regression model for predicting survival. A previously proposed six-tier grading system for level of lung function did not show much separation in survival risk in the less severe grades. A new four-tier grading based on z-scores of -1.645, -3 and -5 showed better separation of risk with hazard ratio for all-cause mortality of 2.0, 3.4 and 6.6 with increasing severity. Using GLI FVC ethnicity methodology to GLI TLco predictions removed ethnic bias and may be the best approach until relevant datasets are available.
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http://dx.doi.org/10.1183/13993003.02046-2020DOI Listing
April 2021

Minimally Invasive Mastectomy Could Achieve Non-inferior Oncological Outcome in Appropriately Selected Patients: Propensity Matched Analysis of the National Cancer Database.

Am Surg 2021 Apr 16:31348211011152. Epub 2021 Apr 16.

Department of Surgery, University Hospitals Cleveland Medical Center and Case Western Reserve School of Medicine, Cleveland, OH, USA.

Background: Minimally invasive mastectomy (MIM) was emerged as an approach to decrease morbidity and increase patient satisfaction through improved cosmetic results; however, there is a paucity of data regarding the long-term oncologic outcomes of these minimally invasive approaches.

Methods: Patients who underwent mastectomy procedures were identified in the National Cancer Database (2010-2016). Patients were categorized as MIM or open mastectomy. A 1:1 propensity match was performed to balance the bias on reconstruction, nipple sparing, lymph node procedures, and other confounding factors between the cohorts. Short- and long-term outcomes were compared.

Results: A total of 328 811 patients met the criteria: 327 643 (99.6%) received open mastectomy and 1168 (.4%) received MIM. Propensity match identified 384 "pairs" of MIM and open mastectomy patients. Among them, MIM was associated with shorter length of stay (LOS) (mean 1.3 vs. 1.06 days, = .003). No differences were observed in the rates of positive margins, unplanned readmissions, or 90-day mortality between the 2 operative approaches. Overall survival (OS) was equivalent between MIM and open mastectomy patients. Cox proportional hazard regression showed no effect of the procedure performed on OS.

Discussion: MIM is associated with shorter LOS, and it is non-inferior to open mastectomy in terms of other short-term outcomes and long-term oncologic survival outcomes. These data suggest that MIM may be considered in appropriately selected breast cancer patients as an additional approach to the community.
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http://dx.doi.org/10.1177/00031348211011152DOI Listing
April 2021

Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibition Reduces Endothelial Cytokine Production without Improving Permeability after Toll-like Receptor 4 (TLR4) Challenge.

Transl Res 2021 Apr 12. Epub 2021 Apr 12.

Department of 1Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232. Electronic address:

Sepsis represents a life-threatening event often mediated by the host's response to pathogens such as gram-negative organisms, which release the pro-inflammatory lipopolysaccharide (LPS). Within the endothelium, the mitogen-activated protein kinase (MAPK) pathway is an important driver of endothelial injury during sepsis, of which oxidant-sensitive apoptosis signal-regulating kinase 1 (ASK1) is postulated to be a critical upstream regulator. We hypothesized that ASK1 would play a key role in endothelial inflammation during bacterial challenge. Utilizing RNA sequencing data from patients and cultured human microvascular endothelial cells (HMVECs), ASK1 expression was increased in sepsis and after LPS challenge. Two ASK1 inhibitors, GS444217 and MSC2023964A, reduced cytokine production in HMVECs following LPS stimulation, but had no effect on permeability as measured by transendothelial electrical resistance (TEER) and intercellular space. MAPKs are known to interact with endothelial nitric oxide synthase (eNOS) and ASK1 expression levels correlated with eNOS expression in patients with septic shock. In addition, eNOS physically interacted with ASK1, though this interaction was not altered by ASK1 inhibition, nor did inhibition alter MAPK p38 activity. Instead, among MAPKs, ASK1 inhibition only impaired LPS-induced JNK phosphorylation. The reduction in JNK activation caused by ASK1 inhibition impaired JNK-mediated cytokine production without affecting permeability. Thus, LPS triggers JNK-dependent cytokine production that requires ASK1 activation, but both its effects on permeability and activation of p38 are ASK1-independent. These data demonstrate how distinct MAPK signaling pathways regulate endothelial inflammatory outputs during acute infectious challenge.
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http://dx.doi.org/10.1016/j.trsl.2021.04.001DOI Listing
April 2021

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Brain 2021 Apr 15. Epub 2021 Apr 15.

Department of Pathology and Cell Biology, Division of Neuropathology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, and the New York Presbyterian Hospital, New York, NY, 10032, USA.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT-PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.
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http://dx.doi.org/10.1093/brain/awab148DOI Listing
April 2021

Risk Factors for Infection and Revision Surgery following Patellar Tendon and Quadriceps Tendon Repairs: An Analysis of 3,442 Patients.

J Knee Surg 2021 Apr 14. Epub 2021 Apr 14.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia.

Disruption of the extensor mechanism is debilitating with surgical repair being the accepted treatment. The incidence of infection and reoperation after extensor mechanism repair are not well reported in the literature. Thus, the objective of the current study was to (1) determine the incidence of surgical site infection and reoperation within 1 year of primary extensor mechanism repair and (2) identify independent risk factors for infection and reoperation following patellar and quadriceps tendon repair. A retrospective review of the 100% Medicare Standard Analytic files from 2005 to 2014 was performed to identify patients undergoing isolated patellar tendon repair and quadriceps tendon repair. Diagnosis of infection within 1 year of operative intervention and revision repair were assessed. Extensor mechanism injuries in the setting of total knee arthroplasty and polytrauma were excluded. Multivariate logistic regression analysis was performed to evaluate risk factors for postoperative infection and reoperation within 1 year. Infection occurred in 6.3% of patients undergoing patellar tendon repair and 2.6% of patients undergoing quadriceps tendon repair. Diabetes mellitus (odds ratio [OR] = 1.89,  = 0.005) was found to be an independent risk factor for infection following patellar tendon repair. Reoperation within 1 year occurred in 1.3 and 3.9% following patellar tendon and quadriceps tendon repair, respectively. Age less than 65 years (OR = 2.77,  = 0.024) and obesity (OR = 3.66,  = 0.046) were significant risk factors for reoperation after patellar tendon repair. Hypertension (OR = 2.13,  = 0.034), hypothyroidism (OR = 2.01,  = 0.010), and depression (OR = 2.41,  = 0.005) were significant risk factors for reoperation after quadriceps tendon repair. Diabetes mellitus was identified as a risk factor for infection after patellar tendon repair. Age less than 65 years, peripheral vascular disease, and congestive heart failure were risk factors for infection after quadriceps tendon repair. The current findings can be utilized to counsel patients regarding preoperative risk factors for postoperative complications prior to surgical intervention for extensor mechanism injuries.
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http://dx.doi.org/10.1055/s-0041-1727113DOI Listing
April 2021

Evidence for avolition in bipolar disorder? A 30-day ecological momentary assessment comparison of daily activities in bipolar disorder and schizophrenia.

Psychiatry Res 2021 Apr 4;300:113924. Epub 2021 Apr 4.

University of Miami Miller School of Medicine, Miami, FL, United States; Bruce W. Carter VA Medical Center, Miami, FL, United States. Electronic address:

Objectives: Disability is common in bipolar disorder (BD) and predicted by persistent sadness. We used ecological momentary assessment (EMA) to examine daily activities in people with BD and schizophrenia. We classified activities as productive, unproductive, or passive recreation, relating them to momentary sadness, location, and social context.

Methods: 71 people with BD and 102 people with schizophrenia were sampled 3 times/day for 30 days with an EMA survey. Each survey asked where they were, with whom, what they were doing, and if they were sad.

Results: People with BD were home more than 50% of the time. There were no differences in prevalence of activity types across diagnoses. People with BD were less likely to report only one activity since the prior survey, but the most surveys still reported only one. For both groups, sadness and being home and alone since the last survey was associated with less productive activity and more passive recreation.

Conclusions: Participants with BD and schizophrenia manifested high levels of unproductive and passive activities, predicted by momentary sadness. These activity patterns are consistent with descriptions of avolition and they minimally differentiated people with BD and schizophrenia. Previous reports of negative symptoms in BD may have been identifying these behaviors.
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http://dx.doi.org/10.1016/j.psychres.2021.113924DOI Listing
April 2021

Effect of "Residents as Teachers" Workshop on Learner Perception of Trainee Teaching Skill.

J Surg Res 2021 Apr 10;264:418-424. Epub 2021 Apr 10.

University Hospitals Cleveland Medical Center, Department of General Surgery, Cleveland Ohio; University Hospitals Research in Surgical Outcomes & Effectiveness Center (UH-RISES), Cleveland Ohio. Electronic address:

Background: Surgical residencies use variable structures for formal training in education. We hypothesized that a one-day workshop intervention would improve resident teaching ability measured by self-assessment and learner evaluation.

Materials And Methods: Faculty educators delivered a Residents as Teachers (RAT) workshop to general surgery residents on setting expectations, positive learning environment, difficult feedback and the 1-min preceptor model. For three months before and after the workshop, junior residents and medical students evaluated their supervising residents' teaching skill monthly using a Likert scale questionnaire. Pre- and postworkshop surveys were administered to resident participants to assess their knowledge of the material and teaching confidence. Results were analyzed using Wilcoxon rank sum tests. This study was conducted at a tertiary academic center with a large surgical residency program.

Results: Thirty-nine PGY 1-5 residents participated in the Residents as Teachers workshop and were included in the study. Pre- and post- workshop survey results demonstrated significant improvements in participants' knowledge and teaching confidence. On monthly assessments of seniors by junior residents, significant improvements were noted in three domains. Medical student ratings did not reflect significant improvements in resident teaching skill.

Conclusions: This is the first study using learner evaluation of a comprehensive surgical RAT program. Despite a significant increase in surgery residents' self-assessment following participation in an education workshop, no improvement was seen in resident teaching skill as perceived by medical students.
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http://dx.doi.org/10.1016/j.jss.2021.02.013DOI Listing
April 2021

Use of Functional Rhinoplasty in the Aging Nose: Medicare Database Analysis.

Facial Plast Surg Aesthet Med 2021 Apr 13. Epub 2021 Apr 13.

Department of Otolaryngology - Head and Neck Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Nasal obstruction is a common clinical problem. It has become more recognized that the internal and external nasal valves are the areas of greatest resistance. There are changes with aging that can contribute to nasal valve compromise. This study sought to evaluate the utilization of functional rhinoplasty, septoplasty, and inferior turbinate reduction procedures in the Medicare population. The annual procedure data were obtained from the Part B National Summary Data File from 2000 to 2019. Functional rhinoplasty procedures using current procedural terminology (CPT) for rhinoplasty (30400, 30410, 30420, 30465), septoplasty (30520), and inferior turbinate reduction (30801, 30802, 30130, 30140, 30930) procedures were analyzed. There was increased use of CPT codes 30465, 30410, and 30420 with a decrease in 30400. There was an overall increase in codes 30520 and 30140. When adjusting for the Medicare population per 100,000 enrollees, there was increased use of 30465 and 30140 and decrease in 30520. The charges and payment trends were similar to the overall use of CPT codes. There is an overall increase in use of nasal airway procedures including functional rhinoplasty in the aging population.
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http://dx.doi.org/10.1089/fpsam.2020.0536DOI Listing
April 2021

Kinetic analysis and optimisation of F-rhPSMA-7.3 PET imaging of prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Apr 12. Epub 2021 Apr 12.

Clinical Research Services Turku - CRST Ltd, Turku, Finland.

Purpose: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer.

Methods: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (K) were calculated using Patlak plots.

Results: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. K, SUV and lesion-to-reference ratio estimates showed good agreement.

Conclusion: F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer.

Trial Registration: NCT03995888 (24 June 2019).
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http://dx.doi.org/10.1007/s00259-021-05346-8DOI Listing
April 2021

Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting.

J Cancer Prev 2021 Mar;26(1):71-82

Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA.

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented.
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http://dx.doi.org/10.15430/JCP.2021.26.1.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020174PMC
March 2021

Development of a physical mobility prediction model to guide prosthetic rehabilitation.

Prosthet Orthot Int 2021 Apr 13. Epub 2021 Apr 13.

Department of Physical Medicine and Rehabilitation, Physical Therapy Program, University of Colorado, Aurora, CO Department of Clinical and Scientific Affairs, Hanger Clinic, Austin, TX Department of Biomechanics, University of Nebraska at Omaha, Omaha, NE Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA Division of Geriatrics, University of California, San Francisco, San Francisco, CA Department of Geriatrics, Geriatric Research, Education, and Clinical Center, VA Eastern Colorado Healthcare System, Aurora, CO Department of Physical Therapy and Rehabilitation Science, University of Montana, Missoula, MT.

Background: Prosthetic rehabilitation decisions depend on estimating a patient's mobility potential. However, no validated prediction models of mobility outcomes exist for people with lower-limb amputation (LLA).

Objectives: To develop and test predictions for self-reported mobility after LLA, using the Prosthetic Limb Users Survey of Mobility (PLUS-M).

Study Design: This is a retrospective cohort analysis.

Methods: Eight hundred thirty-one patient records (1,860 PLUS-M observations) were used to develop and test a neighbors-based prediction model, using previous patient data to predict the 6-month PLUS-M T-score trajectory for a new patient (based on matching characteristics). The prediction model was developed in a training data set (n = 552 patients) and tested in an out-of-sample data set of 279 patients with later visit dates. Prediction performance was assessed using bias, coverage, and precision. Prediction calibration was also assessed.

Results: The average prediction bias for the model was 0.01 SDs, average coverage was 0.498 (ideal proportion within the 50% prediction interval = 0.5), and prediction interval was 8.4 PLUS-M T-score points (40% improvement over population-level estimates). Predictions were well calibrated, with the median predicted scores falling within the standard error of the median of observed scores, across all deciles of the data.

Conclusions: This neighbors-based prediction approach allows for accurate estimates of PLUS-M T-score trajectories for people with LLA.
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http://dx.doi.org/10.1097/PXR.0000000000000001DOI Listing
April 2021

Barriers to atrial fibrillation ablation during mitral valve surgery.

J Thorac Cardiovasc Surg 2021 Mar 17. Epub 2021 Mar 17.

Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative, Ann Arbor, Mich; Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich.

Background: Nearly 40% of patients with atrial fibrillation (AF) undergoing mitral valve surgery do not receive concomitant ablation despite societal guidelines. We assessed barriers to implementation of this evidence-based practice through a survey of cardiac surgeons in 2 statewide quality collaboratives.

Methods: Adult cardiac surgeons across 2 statewide collaboratives were surveyed on their knowledge and practice regarding AF ablation. Questions concerning experience, clinical practice, case scenarios, and barriers to implementation were included.

Results: Among 66 respondents (66 of 135; 48.9%), the majority reported "very comfortable/frequently use" cryoablation (53 of 66; 80.3%) and radiofrequency (55 of 66; 83.3%). Only 12.1% (8/66) were not aware of the recommendations. Approximately one-half of the respondents reported learning AF ablation in fellowship (50.0%; 33 of 66) or attending courses (47.0%; 31 of 66). Responses to clinical scenarios demonstrated wide variability in practice patterns. One-half of the respondents reported no barriers; others cited increased cross-clamp time, excessive patient risk, and arrhythmia incidence as obstacles. Desired interventions included cardiology/electrophysiology support, protocols, pacemaker rate information, and education in the form of site visits, videos and proctors.

Conclusions: Knowledge of evidence-based recommendations and practice patterns vary widely. These data identify several barriers to implementation of concomitant AF ablation and suggest specific interventions (mentorship/support, protocols, research, and education) to overcome these barriers.
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http://dx.doi.org/10.1016/j.jtcvs.2021.03.039DOI Listing
March 2021

Correction to: Integrating Transwomen and Female Athletes with Differences of Sex Development (DSD) into Elite Competition: The FIMS 2021 Consensus Statement.

Sports Med 2021 Apr 9. Epub 2021 Apr 9.

Centre for Exercise Sciences and Sports Medicine, FIMS Collaborating Centre of Sports Medicine, Rome, Italy.

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http://dx.doi.org/10.1007/s40279-021-01467-0DOI Listing
April 2021

Effects of High-Fructose Diet . Teklad Diet in the MNU-Induced Rat Mammary Cancer Model: Altered Tumorigenesis, Metabolomics and Tumor RNA Expression.

J Obes Chronic Dis 2021 11;5(1):67-78. Epub 2021 Jan 11.

Chemopreventive Agent Development Research Group, Division of Cancer Prevention, Rockville, MD.

Epidemiology, clinical and experimental animal studies suggest high fructose diets are detrimental to metabolic status and may contribute to tumor development. This due to increased obesity and metabolic syndrome, known risk factors for many types of cancer. We compared tumor development in N-methyl-N-nitrosourea (MNU)-treated rats fed either a high (60%)-fructose diet (HFD) or a standard diet (SD). Female Sprague-Dawley rats at 43 days of age (DOA) were fed a SD or HFD followed by administration of MNU at 50 DOA. Rats were palpated weekly and sacrificed at 190 DOA. MNU-treated rats on HFD exhibited decreased tumor latency and roughly a two-fold increase in tumor multiplicity. RNA-Seq on frozen tumors (SD HFD rats) showed altered expression of approximately 10% of genes (P < 0.05). When examined by Ingenuity Pathway Analysis, multiple highly significant pathways were identified including A) mechanisms of cancer, B) Wnt pathway, C) immune response (, "Th1 and Th2 activation" and "antigen presentation") and D) LXR/RXR nuclear receptor. These generalized pathways were indirectly confirmed by alterations of various interrelated disease pathways (epithelial cancers, T cell numbers and apoptosis). In a second study, serum was collected from rats on the HFD or SD pre-MNU and at the time of sacrifice. Metabolomics revealed that the HFD yielded: A) increased levels of fructose, B) increases of various monoglycerols, C) reduced levels of various diacylglycerols and oxygenated inflammatory lipids (9 and 13 HODE and 12,13 DHOME) and D) increased levels of secondary bile acids (hyodeoxycholate and 6-oxolithocholate), which may reflect microbiome changes. These metabolomic changes, which are distinct from those on a high-fat diet, may prove relevant when examining individuals who consume higher levels of fructose.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026172PMC
January 2021

Detection of chronic wasting disease in mule and white-tailed deer by RT-QuIC analysis of outer ear.

Sci Rep 2021 Apr 8;11(1):7702. Epub 2021 Apr 8.

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.

Efforts to contain the spread of chronic wasting disease (CWD), a fatal, contagious prion disease of cervids, would be aided by the availability of additional diagnostic tools. RT-QuIC assays allow ultrasensitive detection of prion seeds in a wide variety of cervid tissues, fluids and excreta. The best documented antemortem diagnostic test involving RT-QuIC analysis targets lymphoid tissue in rectal biopsies. Here we have tested a more easily accessed specimen, ear pinna punches, using an improved RT-QuIC assay involving iron oxide magnetic extraction to detect CWD infections in asymptomatic mule and white-tailed deer. Comparison of multiple parts of the ear pinna indicated that a central punch spanning the auricular nerve provided the most consistent detection of CWD infection. When compared to results obtained from gold-standard retropharyngeal lymph node specimens, our RT-QuIC analyses of ear samples provided apparent diagnostic sensitivity (81%) and specificity (91%) that rivaled, or improved upon, those observed in previous analyses of rectal biopsies using RT-QuIC. These results provide evidence that RT-QuIC analysis of ear pinna punches may be a useful approach to detecting CWD infections in cervids.
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http://dx.doi.org/10.1038/s41598-021-87295-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032746PMC
April 2021

Effect of Tibial Tunnel Placement Using the Lateral Meniscus as a Landmark on Clinical Outcomes of Anatomic Single-Bundle Anterior Cruciate Ligament Reconstruction.

Am J Sports Med 2021 Apr 8:363546521999672. Epub 2021 Apr 8.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA.

Background: It remains unclear if use of the lateral meniscus anterior horn (LMAH) as a landmark will produce consistent tunnel positions in the anteroposterior (AP) distance across the tibial plateau.

Purpose: To evaluate the AP location of anterior cruciate ligament (ACL) reconstruction tibial tunnels utilizing the LMAH as an intra-articular landmark and to examine how tunnel placement affects knee stability and clinical outcomes.

Study Design: Cohort study; Level of evidence, 3.

Methods: A retrospective review was conducted of 98 patients who underwent primary ACL reconstruction with quadrupled hamstring tendon autografts between March 2013 and June 2017. Patients with unilateral ACL injuries and a minimum follow-up of 2 years were included in the study. All guide pins for the tibial tunnel were placed using the posterior border of the LMAH as an intra-articular landmark. Guide pins were evaluated with the Bernard-Hertel grid in the femur and the Stäubli-Rauschning method in the tibia. Patients were divided by the radiographic location of the articular entry point of the guide pin with relation to the anterior 40% of the tibial plateau. Outcomes were evaluated by the Marx Activity Scale and International Knee Documentation Committee (IKDC) form. Anterior knee laxity was evaluated using a KT-1000 arthrometer and graded with the objective portion of the IKDC form. Rotational stability was evaluated using the pivot-shift test.

Results: A total of 60 patients were available for follow-up at a mean 28.6 months. The overall percentage of AP placement of the tibial tunnel was 39.3% ± 3.8% (mean ± SD; range, 31%-47%). Side-to-side difference of anterior knee laxity was significantly lower in the anterior group than the posterior group (1.2 ± 1.1 mm vs 2.5 ± 1.3 mm; < .001; = 0.51). The percentage of AP placement of the tibial tunnel demonstrated a positive medium correlation with side-to-side difference of anterior knee laxity as measured by a KT-1000 arthrometer ( = 0.430; < .001). The anterior group reported significantly better distribution of IKDC grading as compared with the posterior group (26 grade A and 6 grade B vs 15 grade A and 13 grade B; = .043; = 0.297). The pivot-shift test results and outcome scores showed no significant differences between the groups.

Conclusion: Using the posterior border of the LMAH as an intraoperative landmark yields a wide range of tibial tunnel locations along the tibial plateau, with anterior placement of the tibial tunnel leading toward improved anterior knee stability.
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http://dx.doi.org/10.1177/0363546521999672DOI Listing
April 2021

EVALUATING THE USE OF A BUTORPHANOL-AZAPERONE-MEDETOMIDINE FIXED-DOSE COMBINATION FOR STANDING SEDATION IN AFRICAN ELEPHANTS ().

J Zoo Wildl Med 2021 Apr;52(1):287-294

Wildlife Pharmaceuticals South Africa (Pty) Ltd, White River, 1240, South Africa.

This study investigated the use of a fixed-dose combination of 30 mg/ml butorphanol, 12 mg/ml azaperone, and 12 mg/ml medetomidine for the standing sedation of captive African elephants (). In total, seven females (mean age 19.6 yr; range 6-31 yr) and six males (mean age 33.5 yr; range 9-35 yr) were sedated. The estimated dose was 0.0005 ± 0.0001 ml/kg and 0.006 ± 0.001 ml/cm shoulder height, which resulted in a dose of 0.016 ± 0.002 mg/kg or 0.19 ± 0.04 mg/cm shoulder height butorphanol, 0.006 ± 0.0008 mg/ kg or 0.076 ± 0.015 mg/cm shoulder height azaperone, and 0.006 ± 0.0008 mg/kg or 0.076 ± 0.015 mg/cm medetomidine. First signs of sedation were observed within 3-10 min (mean 6 ± 2 min) after darting, and monitoring of the animals started on average at 24 ± 9 min after darting. No bradycardia was observed in any of the elephants (mean heart rate 40.0 ± 6.55 beats/min), although all the animals were mildly hypotensive (mean blood pressure 118.5/86 [94.5]). Rectal temperatures fell within acceptable ranges, and respiratory parameters were stable in all the animals throughout sedation and fell within the standard ranges reported for conscious, standing elephants. Only one elephant had clinically significant hypoxemia characterized by a partial pressure of oxygen (PaO) < 60 mm Hg. This elephant was also hypercapnic (PaCO > 50 mm Hg), although pH and peripheral capillary oxygen saturation fell within acceptable ranges. None of the elephants reacted to moderately painful stimuli while sedated. The combination was reversed with intramuscular injections of naltrexone (1 mg for every 1 mg butorphanol) and atipamezole (5 mg for every 1 mg medetomidine). Recovery was smooth and calm in all the animals. Time from injection of the reversals until the first signs of recovery was 4.6 ± 2.01 min (range 1-8 min).
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http://dx.doi.org/10.1638/2019-0185DOI Listing
April 2021

While Woolworths reaps the rewards, the Northern Territory community will be left to clean up the mess.

Health Promot J Austr 2021 Apr 6. Epub 2021 Apr 6.

Wellbeing and Preventable Chronic Diseases Division, Menzies School of Health Research, Darwin, Australia.

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http://dx.doi.org/10.1002/hpja.488DOI Listing
April 2021

Despite Equivalent Outcomes, Men Receive Neoadjuvant Chemotherapy Less Often Than Women for Lymph Node-Positive Breast Cancer.

Ann Surg Oncol 2021 Apr 6. Epub 2021 Apr 6.

Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Background: Neoadjuvant chemotherapy (NAC) downstages breast cancer and provides prognostic information. Males with breast cancer are known to receive less treatment overall and have poorer outcomes relative to females. We hypothesized that males would be less likely to receive NAC.

Patients And Methods: Patients with a primary diagnosis of cN1-3 breast cancer were identified in the National Cancer Database (2004-2016). Multivariable logistic regression determined the association between NAC utilization and sex, and the relationship between sex and NAC response, controlling for demographic and tumor factors. Overall survival was analyzed using a multivariable Cox model.

Results: In total, 196,027 patients (194,010 females, 2017 males) met inclusion criteria. A significantly greater proportion of males underwent mastectomy (80% vs. 60%, P < 0.001), and axillary lymph node dissection (76% vs. 74%, P = 0.022). Overall fewer men received chemotherapy than women (73% vs. 84%, P < 0.001); men also received NAC at a significantly lower rate (26% men vs. 45% women, P < 0.001). After accounting for demographic and oncologic factors including hormone receptor (HR) subtype, females remained more likely to undergo NAC (OR 1.84, P < 0.001). On multivariable analysis, sex was not associated with pathologic response or overall survival after NAC.

Conclusions: Although oncologic outcomes after NAC were similar, males with node-positive breast cancer received less NAC and more aggressive surgery than females. These data suggest men achieve outcomes comparable to women with cN1-3 disease, and NAC should be used in appropriate male patients to downstage the breast and axilla.
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http://dx.doi.org/10.1245/s10434-021-09857-4DOI Listing
April 2021

OPPORTUNISTIC SURVEILLANCE OF CAPTIVE AND FREE-RANGING BIGHORN SHEEP (OVIS CANADENSIS) IN COLORADO, USA, FOR TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES.

J Wildl Dis 2021 Apr;57(2):338-344

Colorado Parks and Wildlife, Wildlife Health Program, 4330 Laporte Avenue, Fort Collins, Colorado 80521, USA.

Bighorn sheep (Ovis canadensis) are predicted to have a degree of susceptibility to the transmissible spongiform encephalopathies (TSE) chronic wasting disease and scrapie. We opportunistically screened 127 captive bighorn sheep and 152 free-ranging bighorn sheep in Colorado, US for the presence of TSE over a period of 35 yr. None of the animals demonstrated clinical signs, gross pathology, histopathology, or immunohistochemical staining patterns suggestive of TSE.
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http://dx.doi.org/10.7589/JWD-D-20-00083DOI Listing
April 2021

Adenovirus Hemorrhagic Disease in Moose (Alces americanus gigas) in Alaska, USA.

J Wildl Dis 2021 Apr;57(2):418-422

Alaska Department of Fish and Game, 3200 College Road, Fairbanks, Alaska 99701, USA.

In 1993, an epizootic of adenovirus hemorrhagic disease (AHD) caused the death of at least 1,000 mule deer (Odocoileus hemionus) in California, US. Since then, numerous cervid species throughout the US have had deaths confirmed to be caused by AHD. In 2015, the death of two captive moose (Alces americanus gigas) calves marked the first recognized AHD-caused deaths in Alaska, a state in which moose are important economically as well as for food security and cultural identity. Both cases were characterized by systemic vasculitis with endothelial cell intranuclear inclusion bodies, pulmonary edema, petechial hemorrhages, and enterotyphlocolitis.
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http://dx.doi.org/10.7589/JWD-D-20-00102DOI Listing
April 2021

DETECTION OF DEER ATADENOVIRUS A DNA IN DAM AND OFFSPRING PAIRS OF ROCKY MOUNTAIN MULE DEER (ODOCOILEUS HEMIONUS HEMIONUS) AND ROCKY MOUNTAIN ELK (CERVUS CANADENSIS NELSONI).

J Wildl Dis 2021 Apr;57(2):313-320

Wyoming State Veterinary Laboratory, University of Wyoming, 1174 Snowy Range Road, Laramie, Wyoming 82070, USA.

Adenovirus hemorrhagic disease affects primarily mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginianus), Rocky Mountain elk (Cervus canadensis nelsoni), and moose (Alces alces) in their first year of life. The method by which the causative virus, Deer atadenovirus A, is maintained in the environment and transmitted to neonates is unknown. In this study, we investigated the potential transmission of the virus from dam to offspring in Rocky Mountain mule deer (Odocoileus hemionus hemionus) and elk in western Wyoming, US. We sampled dams before parturition during placement of vaginal implant transmitters and at parturition and sampled neonates during capture in their first days of life. We also tested for the virus in mortalities submitted for pathologic examination and laboratory analysis. We detected viral DNA in samples from all time points tested but did not find a connection between positive dams and offspring mortalities associated with adenovirus hemorrhagic disease. Although we did not find direct evidence of transmission events between dams and offspring, asymptomatic animals shedding of Deer atadenovirus A, are a likely source of infection in neonates.
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http://dx.doi.org/10.7589/JWD-D-20-00034DOI Listing
April 2021

THE PULMONARY AND METABOLIC EFFECTS OF SUSPENSION BY THE FEET COMPARED WITH LATERAL RECUMBENCY IN IMMOBILIZED BLACK RHINOCEROSES (DICEROS BICORNIS) CAPTURED BY AERIAL DARTING.

J Wildl Dis 2021 Apr;57(2):357-367

Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, 930 Campus Road, Ithaca, New York 14853, USA.

Aerial translocation of captured black rhinoceroses (Diceros bicornis) has been accomplished by suspending them by their feet. We expected this posture would compromise respiratory gas exchange more than would lateral recumbency. Because white rhinoceroses (Ceratotherium simum) immobilized with etorphine alone are hypermetabolic, with a high rate of carbon dioxide production (VCO2), we expected immobilized black rhinoceroses would also have a high VCO2. Twelve (nine male, three female; median age 8 yr old [range: 4-25]; median weight 1,137 kg [range: 804-1,234] body weight) wild black rhinoceroses were immobilized by aerial darting with etorphine and azaperone. The animals were in lateral recumbency or suspended by their feet from a crane for approximately 10 min before data were collected. Each rhinoceros received both treatments sequentially, in random order. Six were in lateral recumbency first and six were suspended first. All animals were substantially hypoxemic and hypercapnic in both postures. When suspended by the feet, mean arterial oxygen pressure (PaO2) was 42 mm Hg, 4 mm Hg greater than in lateral recumbency (P=0.030), and arterial carbon dioxide pressure (PaCO2) was 52 mm Hg, 3 mm Hg less than in lateral recumbency (P=0.016). Tidal volume and minute ventilation were similar between postures. The mean VCO2 was 2 mL/kg/min in both postures and was similar to, or marginally greater than, VCO2 predicted allometrically. Suspension by the feet for 10 min did not impair pulmonary function more than did lateral recumbency and apparently augmented gas exchange to a small degree relative to lateral recumbency. The biological importance in these animals of numerically small increments in PaO2 and decrements in PaCO2 with suspension by the feet is unknown. Black rhinoceroses immobilized with etorphine and azaperone were not as hypermetabolic as were white rhinoceroses immobilized with etorphine.
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http://dx.doi.org/10.7589/2019-08-202DOI Listing
April 2021

An observational study to develop a scoring system and model to detect risk of hospital admission due to COVID-19.

J Am Coll Emerg Physicians Open 2021 Apr 31;2(2):e12406. Epub 2021 Mar 31.

Department of Emergency and Hospital Medicine/USF Morsani College of Medicine, Lehigh Valley Health Network Allentown Pennsylvania USA.

Background: COVID-19 has caused an unprecedented global health emergency. The strains of such a pandemic can overwhelm hospital capacity. Efficient clinical decision-making is crucial for proper healthcare resource utilization in this crisis. Using observational study data, we set out to create a predictive model that could anticipate which COVID-19 patients would likely be admitted and developed a scoring tool that could be used in the clinical setting and for population risk stratification.

Methods: We retrospectively evaluated data from COVID-19 patients across a network of 6 hospitals in northeastern Pennsylvania. Analysis was limited to age, gender, and historical variables. After creating a variable importance plot, we chose a selection of the best predictors to train a logistic regression model. Variable selection was done using a lasso regularization technique. Using the coefficients in our logistic regression model, we then created a scoring tool and validated the score on a test set data.

Results: A total of 6485 COVID-19 patients were included in our analysis, of which 707 were hospitalized. The biggest predictors of patient hospitalization included age, a history of hypertension, diabetes, chronic heart disease, gender, tobacco use, and chronic kidney disease. The logistic regression model demonstrated an AUC of 0.81. The coefficients for our logistic regression model were used to develop a scoring tool. Low-, intermediate-, and high-risk patients were deemed to have a 3.5%, 26%, and 38% chance of hospitalization, respectively. The best predictors of hospitalization included age (odds ratio [OR] = 1.03, confidence interval [CI] = 1.02-1.03), diabetes (OR = 2.08, CI = 1.69-2.57), hypertension (OR = 2.36, CI = 1.90-2.94), chronic heart disease (OR = 1.53, CI = 1.22-1.91), and male gender (OR = 1.32, CI = 1.11-1.58).

Conclusions: Using retrospective observational data from a 6-hospital network, we determined risk factors for admission and developed a predictive model and scoring tool for use in the clinical and population setting that could anticipate admission for COVID-19 patients.
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http://dx.doi.org/10.1002/emp2.12406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011617PMC
April 2021

Low Diversity of Human Variation Despite Mostly Mild Functional Impact of De Novo Variants.

Front Mol Biosci 2021 18;8:635382. Epub 2021 Mar 18.

Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ, United States.

Non-synonymous Single Nucleotide Variants (nsSNVs), resulting in single amino acid variants (SAVs), are important drivers of evolutionary adaptation across the tree of life. Humans carry on average over 10,000 SAVs per individual genome, many of which likely have little to no impact on the function of the protein they affect. Experimental evidence for protein function changes as a result of SAVs remain sparse - a situation that can be somewhat alleviated by predicting their impact using computational methods. Here, we used SNAP to examine both and generated human variation in a set of 1,265 proteins that are consistently found across a number of diverse species. The number of SAVs that are predicted to have any functional effect on these proteins is smaller than expected, suggesting sequence/function optimization over evolutionary timescales. Additionally, we find that only a few of the yet-unobserved SAVs could drastically change the function of these proteins, while nearly a quarter would have only a mild functional effect. We observed that variants common in the human population localized to less conserved protein positions and carried mild to moderate functional effects more frequently than rare variants. As expected, rare variants carried severe effects more frequently than common variants. In line with current assumptions, we demonstrated that the change of the human reference sequence amino acid to the reference of another species (a cross-species variant) is unlikely to significantly impact protein function. However, we also observed that many cross-species variants may be weakly non-neutral for the purposes of quick adaptation to environmental changes, but may not be identified as such by current state-of-the-art methodology.
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http://dx.doi.org/10.3389/fmolb.2021.635382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012514PMC
March 2021

ER71/ETV2 Promotes Hair Regeneration from Chemotherapeutic Drug-Induced Hair Loss by Enhancing Angiogenesis.

Biomol Ther (Seoul) 2021 Apr 5. Epub 2021 Apr 5.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. conditional knockout (CKO) mice, which lack in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.
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http://dx.doi.org/10.4062/biomolther.2021.022DOI Listing
April 2021