Publications by authors named "Michael Miller"

2,213 Publications

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Towards single-chip radiofrequency signal processing via acoustoelectric electron-phonon interactions.

Nat Commun 2021 May 13;12(1):2769. Epub 2021 May 13.

Microsystems Engineering, Science, and Applications, Sandia National Laboratories, Albuquerque, NM, USA.

The addition of active, nonlinear, and nonreciprocal functionalities to passive piezoelectric acoustic wave technologies could enable all-acoustic and therefore ultra-compact radiofrequency signal processors. Toward this goal, we present a heterogeneously integrated acoustoelectric material platform consisting of a 50 nm indium gallium arsenide epitaxial semiconductor film in direct contact with a 41° YX lithium niobate piezoelectric substrate. We then demonstrate three of the main components of an all-acoustic radiofrequency signal processor: passive delay line filters, amplifiers, and circulators. Heterogeneous integration allows for simultaneous, independent optimization of the piezoelectric-acoustic and electronic properties, leading to the highest performing surface acoustic wave amplifiers ever developed in terms of gain per unit length and DC power dissipation, as well as the first-ever demonstrated acoustoelectric circulator with an isolation of 46 dB with a pulsed DC bias. Finally, we describe how the remaining components of an all-acoustic radiofrequency signal processor are an extension of this work.
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http://dx.doi.org/10.1038/s41467-021-22935-1DOI Listing
May 2021

Brain Somatic Mutation in Aging and Alzheimer's Disease.

Annu Rev Genomics Hum Genet 2021 May 12. Epub 2021 May 12.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; email:

Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, including in the brain. Technological advances in nucleic acid sequencing have enabled recent breakthroughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer's disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD. Expected final online publication date for the , Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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http://dx.doi.org/10.1146/annurev-genom-121520-081242DOI Listing
May 2021

Inferring Chronic Wasting Disease Incidence from Prevalence Data.

J Wildl Dis 2021 May 7. Epub 2021 May 7.

Colorado Division of Parks and Wildlife, 4330 Laporte Avenue, Fort Collins, Colorado 80521-2153, USA.

Incidence of chronic wasting disease infection showed strong, positive correlation (r≥0.944) with apparent prevalence among female and male mule deer (Odocoileus hemionus) in seven herds previously studied in Colorado and Wyoming, USA. With attention to monitoring method consistency and context, inferring that observed prevalence trends reflect underlying epidemic dynamics in mule deer herds appears justifiable.
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http://dx.doi.org/10.7589/JWD-D-20-00216DOI Listing
May 2021

Predictors of preference for cognitive-behavioral therapy (CBT) and yoga interventions among older adults.

J Psychiatr Res 2021 Mar 30;138:311-318. Epub 2021 Mar 30.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, United States. Electronic address:

The purpose of this study was to examine factors that influence a person's choice of cognitive-behavioral therapy (CBT) or yoga, the stability of these preferences, and the impact of preference on engagement and process measures. We conducted a randomized preference trial of CBT and yoga in 500 adults ≥60 years with symptoms of worry. Participants reported their intervention preference, strength of preference, and factors impacting preference. Engagement in the intervention (session completion and dropout rates) was assessed. Process measures included satisfaction with the intervention, therapeutic alliance, and intervention expectancy. Neither intervention preference (48% and 52% chose CBT and yoga, respectively) nor strength of preference differed significantly between the two preference trial groups. Intervention expectancies at baseline among those in the preference trial were approximately 4.5 units (40-point scale) higher for their preferred intervention (p < .0001 within each group). A principal component analysis of factors influencing preference identified three constructs. Using logistic regression, components focused on attitudes about CBT or yoga were predictive of ultimate preference (odds ratio = 11.5, 95% C.I.6.3-21.0 per 1SD difference in component 1 for choosing CBT; odds ratio = 7.8, 95% CI4.3-13.9 per 1SD difference in component 2 for choosing yoga). There were no significant differences between the randomized and preference trials on intervention adherence, completion of assessments, intervention satisfaction, or working alliance. Receiving a preferred treatment had no significant effects on intervention outcomes through participant engagement or process measures. When options are limited, providers may have confidence in offering the most readily available non-pharmacological treatments.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.055DOI Listing
March 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 20. Epub 2021 Apr 20.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. 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 proinflammatory 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 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083258PMC
April 2021

Counterpoint regarding an alternative hypothesis for why exposure to static magnetic and electric fields treat type 2 diabetes.

Am J Physiol Endocrinol Metab 2021 Apr 12. Epub 2021 Apr 12.

Radiation Oncology, Univerisity of Iowa.

Petersen et al. hypothesize that vestibular stress underlies the therapeutic effects of static magnetic and electric fields in type 2 diabetes. However, our experimental data directly contradict the predictions made by this alternative hypothesis. Here, we discuss key findings that support a mechanism that is independent of vestibular stress to explain the remarkable insulin sensitizing effects of static magnetic and electric fields. Our findings are consistent with a redox-dependent mechanism that involves mitochondrial oxidants in liver and the induction of an insulin sensitizing redox response.
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http://dx.doi.org/10.1152/ajpendo.00110.2021DOI Listing
April 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

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

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

Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk.

Nat Genet 2021 04 1;53(4):455-466. Epub 2021 Apr 1.

Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.

Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
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http://dx.doi.org/10.1038/s41588-021-00823-0DOI Listing
April 2021

Detection and Profiling of Human Coronavirus Immunoglobulins in Critically Ill Coronavirus Disease 2019 Patients.

Crit Care Explor 2021 Mar 12;3(3):e0369. Epub 2021 Mar 12.

Thermo Fisher Scientific, Rockford, IL.

Objectives: Coronavirus disease 2019 continues to spread worldwide with high levels of morbidity and mortality. We performed anticoronavirus immunoglobulin G profiling of critically ill coronavirus disease 2019 patients to better define their underlying humoral response.

Design: Blood was collected at predetermined ICU days to measure immunoglobulin G with a research multiplex assay against four severe acute respiratory syndrome coronavirus 2 proteins/subunits and against all six additionally known human coronaviruses.

Setting: Tertiary care ICU and academic laboratory.

Subjects: ICU patients suspected of being infected with severe acute respiratory syndrome coronavirus 2 had blood collected until either polymerase chain reaction testing was confirmed negative on ICU day 3 (coronavirus disease 2019 negative) or until death or discharge if the patient tested polymerase chain reaction positive (coronavirus disease 2019 positive).

Interventions: None.

Measurements And Main Results: Age- and sex-matched healthy controls and ICU patients who were either coronavirus disease 2019 positive or coronavirus disease 2019 negative were enrolled. Cohorts were well-balanced with the exception that coronavirus disease 2019 positive patients had greater body mass indexes, presented with bilateral pneumonias more frequently, and suffered lower Pao:Fio ratios, when compared with coronavirus disease 2019 negative patients ( < 0.05). Mortality rate for coronavirus disease 2019 positive patients was 50%. On ICU days 1-3, anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G was significantly elevated in coronavirus disease 2019 positive patients, as compared to both healthy control subjects and coronavirus disease 2019 negative patients ( < 0.001). Weak severe acute respiratory syndrome coronavirus immunoglobulin G serologic responses were also detected, but not other coronavirus subtypes. The four anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G were maximal by ICU day 3, with all four anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G providing excellent diagnostic potential (severe acute respiratory syndrome coronavirus 2 Spike 1 protein immunoglobulin G, area under the curve 1.0, < 0.0005; severe acute respiratory syndrome coronavirus receptor binding domain immunoglobulin G, area under the curve, 0.93-1.0; ≤ 0.0001; severe acute respiratory syndrome coronavirus 2 Spike proteins immunoglobulin G, area under the curve, 1.0; < 0.0001; severe acute respiratory syndrome coronavirus 2 Nucleocapsid protein immunoglobulin G area under the curve, 0.90-0.95; ≤ 0.0003). Anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G increased and/or plateaued over 10 ICU days.

Conclusions: Critically ill coronavirus disease 2019 patients exhibited anti-severe acute respiratory syndrome coronavirus 2 immunoglobulin G, whereas serologic responses to non-severe acute respiratory syndrome coronavirus 2 antigens were weak or absent. Detection of human coronavirus immunoglobulin G against the different immunogenic structural proteins/subunits with multiplex assays may be useful for pathogen identification, patient cohorting, and guiding convalescent plasma therapy.
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http://dx.doi.org/10.1097/CCE.0000000000000369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994038PMC
March 2021

The COVIDome Explorer Researcher Portal.

medRxiv 2021 Mar 8. Epub 2021 Mar 8.

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. In order to expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients including matched analysis of the whole blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate here the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.
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http://dx.doi.org/10.1101/2021.03.04.21252945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987038PMC
March 2021

Design and Testing of Stimulation and Myoelectric Recording Modules in an Implanted Distributed Neuroprosthetic System.

IEEE Trans Biomed Circuits Syst 2021 Mar 17;PP. Epub 2021 Mar 17.

Implantable motor neuroprostheses can restore functionality to individuals with neurological disabilities by electrically activating paralyzed muscles in coordinated patterns. The typical design of neuroprosthetic systems relies on a single multi-use device, but this limits the number of stimulus and sensors channels that can be practically implemented. To address this limitation, a modular neuroprosthesis, the Networked Neuroprosthesis (NNP), was developed. The NNP system is the first fully implanted modular neuroprosthesis that includes implantation of all power, signal processing, biopotential signal recording, and stimulating components. This paper describes the design of stimulation and recording modules, bench testing to verify stimulus outputs and appropriate filtering and recording, and validation that the components function properly while implemented in persons with spinal cord injury. The results of system testing demonstrated that the NNP was functional and capable of generating stimulus pulses and recording myoelectric, temperature, and accelerometer signals. Based on the successful design, manufacturing, and testing of the NNP System, multiple clinical applications are anticipated.
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http://dx.doi.org/10.1109/TBCAS.2021.3066838DOI Listing
March 2021

Ensuring Yoga Intervention Fidelity in a Randomized Preference Trial for the Treatment of Worry in Older Adults.

J Altern Complement Med 2021 Mar 8. Epub 2021 Mar 8.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Yoga for treatment of worry in older adults is an intervention that is especially likely to translate into real-world practice. Assessing treatment fidelity improves confidence that effective interventions can be consistently applied and allows researchers to explore if any null results for effectiveness are indeed the result of a lack of intervention efficacy or lack of proper intervention implementation. This study describes treatment fidelity of a yoga intervention in a randomized preference trial that compared cognitive-behavioral therapy (CBT) and yoga for the treatment of worry, anxiety, and sleep in worried older (≥60 years) adults. Established methods for assessing treatment fidelity of CBT guided the procedure for ensuring that the yoga intervention was delivered as intended. The yoga intervention consisted of 20, 75-min, in-person, group, gentle yoga classes held twice weekly. Six female instructors (mean age = 64 years) taught 660 yoga classes that were videotaped. Ten percent of these classes, stratified by instructor, were randomly selected for review. The average adherence score for yoga instructors was 6.84 (range 4-8). The average competency scores were consistently high, with an average score of 7.24 (range 6-8). Teaching content not included in the protocol occurred in 26 (38.1%) sessions and decreased over time. Observed ratings of instructor adherence were significantly related to ratings of competency. Instructor adherence was also significantly associated with lower participant attendance, but not with any of the other process or outcome measures. The larger range found in adherence relative to competence scores demonstrated that teaching a yoga class according to a protocol requires different skills than competently teaching a yoga class in the community, and these skills improved with feedback. These results may foster dialog between the yoga research and practice communities. Clinical Trial Registration No.: NCT02968238.
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http://dx.doi.org/10.1089/acm.2020.0476DOI Listing
March 2021

A case study of ascertainment bias for the primary outcome in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial.

Clin Trials 2021 Apr 7;18(2):207-214. Epub 2021 Mar 7.

Yale Center for Analytical Sciences, Yale University, New Haven, CT, USA.

Background/aim: In clinical trials, there is potential for bias from unblinded observers that may influence ascertainment of outcomes. This issue arose in the Strategies to Reduce Injuries and Develop Confidence in Elders trial, a cluster randomized trial to test a multicomponent intervention versus enhanced usual care (control) to prevent serious fall injuries, originally defined as a fall injury leading to medical attention. An unblinded nurse falls care manager administered the intervention, while the usual care arm did not involve contact with a falls care manager. Thus, there was an opportunity for falls care managers to refer participants reporting falls to seek medical attention. Since this type of observer bias could not occur in the usual care arm, there was potential for additional falls to be reported in the intervention arm, leading to dilution of the intervention effect and a reduction in study power. We describe the clinical basis for ascertainment bias, the statistical approach used to assess it, and its effect on study power.

Methods: The prespecified interim monitoring plan included a decision algorithm for assessing ascertainment bias and adapting (revising) the primary outcome definition, if necessary. The original definition categorized serious fall injuries requiring medical attention into Type 1 (fracture other than thoracic/lumbar vertebral, joint dislocation, cut requiring closure) and Type 2 (head injury, sprain or strain, bruising or swelling, other). The revised definition, proposed by the monitoring plan, excluded Type 2 injuries that did not necessarily require an overnight hospitalization since these would be most subject to bias. These injuries were categorized into those with (Type 2b) and without (Type 2c) medical attention. The remaining Type 2a injuries required medical attention and an overnight hospitalization. We used the ratio of 2b/(2b + 2c) in intervention versus control as a measure of ascertainment bias; ratios > 1 indicated the likelihood of falls care manager bias. We determined the effect of ascertainment bias on study power for the revised (Types 1 and 2a) versus original definition (Types 1, 2a, and 2b).

Results: The estimate of ascertainment bias was 1.14 (95% confidence interval: 0.98, 1.30), providing evidence of the likelihood of falls care manager bias. We estimated that this bias diluted the hazard ratio from the hypothesized 0.80 to 0.86 and reduced power to under 80% for the original primary outcome definition. In contrast, adapting the revised definition maintained study power at nearly 90%.

Conclusion: There was evidence of ascertainment bias in the Strategies to Reduce Injuries and Develop Confidence in Elders trial. The decision to adapt the primary outcome definition reduced the likelihood of this bias while preserving the intervention effect and study power.
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http://dx.doi.org/10.1177/1740774520980070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009806PMC
April 2021

HUNTING PRESSURE MODULATES PRION INFECTION RISK IN MULE DEER HERDS.

J Wildl Dis 2020 10;56(4):781-790

Colorado Division of Parks and Wildlife, 317 W Prospect Road, Fort Collins, Colorado 80526-2097, USA.

The emergence of chronic wasting disease, an infectious prion disease of multiple deer species, has motivated international calls for sustainable, socially accepted control measures. Here, we describe long-term, spatially replicated relationships in Colorado, US, mule deer (Odocoileus hemionus) herds that show hunting pressure can modulate apparent epidemic dynamics as reflected by prevalence trends. Across 12 areas in Colorado studied between 2002-18, those with the largest declines in annual hunting license numbers (pressure) showed the largest increases in the proportion of infected adult (≥2-yr-old) male deer killed by hunters (prevalence); prevalence trends were comparatively flat in most areas where license numbers had been maintained or increased. The mean number of licenses issued in the 2 yr prior best explained observed patterns: increasing licenses lowered subsequent risk of harvesting an infected deer, and decreasing licenses increased that risk. Our findings suggest that harvesting mule deer with sufficient hunting pressure might control chronic wasting disease-especially when prevalence is low-but that harvest prescriptions promoting an abundance of mature male deer contribute to the exponential growth of epidemics.
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http://dx.doi.org/10.7589/JWD-D-20-00054DOI Listing
October 2020

MIPP-Seq: ultra-sensitive rapid detection and validation of low-frequency mosaic mutations.

BMC Med Genomics 2021 Feb 12;14(1):47. Epub 2021 Feb 12.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Center for Life Sciences 15062, 300 Longwood Avenue, BCH3150, Boston, MA, 02115, USA.

Background: Mosaic mutations contribute to numerous human disorders. As such, the identification and precise quantification of mosaic mutations is essential for a wide range of research applications, clinical diagnoses, and early detection of cancers. Currently, the low-throughput nature of single allele assays (e.g., allele-specific ddPCR) commonly used for genotyping known mutations at very low alternate allelic fractions (AAFs) have limited the integration of low-level mosaic analyses into clinical and research applications. The growing importance of mosaic mutations requires a more rapid, low-cost solution for mutation detection and validation.

Methods: To overcome these limitations, we developed Multiple Independent Primer PCR Sequencing (MIPP-Seq) which combines the power of ultra-deep sequencing and truly independent assays. The accuracy of MIPP-seq to quantifiable detect and measure extremely low allelic fractions was assessed using a combination of SNVs, insertions, and deletions at known allelic fractions in blood and brain derived DNA samples.

Results: The Independent amplicon analyses of MIPP-Seq markedly reduce the impact of allelic dropout, amplification bias, PCR-induced, and sequencing artifacts. Using low DNA inputs of either 25 ng or 50 ng of DNA, MIPP-Seq provides sensitive and quantitative assessments of AAFs as low as 0.025% for SNVs, insertion, and deletions.

Conclusions: MIPP-Seq provides an ultra-sensitive, low-cost approach for detecting and validating known and novel mutations in a highly scalable system with broad utility spanning both research and clinical diagnostic testing applications. The scalability of MIPP-Seq allows for multiplexing mutations and samples, which dramatically reduce costs of variant validation when compared to methods like ddPCR. By leveraging the power of individual analyses of multiple unique and independent reactions, MIPP-Seq can validate and precisely quantitate extremely low AAFs across multiple tissues and mutational categories including both indels and SNVs. Furthermore, using Illumina sequencing technology, MIPP-seq provides a robust method for accurate detection of novel mutations at an extremely low AAF.
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http://dx.doi.org/10.1186/s12920-021-00893-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881461PMC
February 2021

Patient experience after modifying visit delivery during the COVID-19 pandemic.

Am J Manag Care 2021 02 1;27(2):e54-e63. Epub 2021 Feb 1.

Mid-Atlantic Permanente Research Institute, 2101 E Jefferson St, Rockville, MD 20852. Email:

Objectives: To describe real-time changes in medical visits (MVs), visit mode, and patient-reported visit experience associated with rapidly deployed care reorganization during the coronavirus disease 2019 (COVID-19) pandemic.

Study Design: Cross-sectional time series from September 29, 2019, through June 20, 2020.

Methods: Responding to official public health and clinical guidance, team-based systematic structural changes were implemented in a large, integrated health system to reorganize and transition delivery of care from office-based to virtual care platforms. Overall and discipline-specific weekly MVs, visit mode (office-based, telephone, or video), and associated aggregate measures of patient-reported visit experience were reported. A 38-week time-series analysis with March 8, 2020, and May 3, 2020, as the interruption dates was performed.

Results: After the first interruption, there was a decreased weekly visit trend for all visits (β3 = -388.94; P < .05), an immediate decrease in office-based visits (β2 = -25,175.16; P < .01), increase in telephone-based visits (β2 = 17,179.60; P < .01), and increased video-based visit trend (β3 = 282.02; P < .01). After the second interruption, there was an increased visit trend for all visits (β5 = 565.76; P < .01), immediate increase in video-based visits (β4 = 3523.79; P < .05), increased office-based visit trend (β5 = 998.13; P < .01), and decreased trend in video-based visits (β5 = -360.22; P < .01). After the second interruption, there were increased weekly long-term visit trends for the proportion of patients reporting "excellent" as to how well their visit needs were met for all visits (β5 = 0.17; P < .01), telephone-based visits (β5 = 0.34; P < .01), and video-based visits (β5 = 0.32; P < .01). Video-based visits had the highest proportion of respondents rating "excellent" as to how well their scheduling and visit needs were met.

Conclusions: COVID-19 required prompt organizational transformation to optimize the patient experience.
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http://dx.doi.org/10.37765/ajmc.2021.88535DOI Listing
February 2021

Laryngeal Mask Airway for Surfactant Administration Versus Standard Treatment Methods in Preterm Neonates with Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

Am J Perinatol 2021 Jan 31. Epub 2021 Jan 31.

Neonatal Division, Department of Pediatrics, Western University, London, Canada.

Objective:  Laryngeal mask airway (LMA) has emerged as an alternative surfactant delivery method. The effectiveness of this method for the delivery of surfactant is uncertain. A meta-analysis of randomized control trials (RCTs) comparing LMA with standard methods of surfactant delivery for the outcomes of surfactant dose repetition, oxygen requirement, mechanical ventilation, intubation, mortality, bronchopulmonary dysplasia (BPD), and pneumothorax.

Study Design:  Systematic review and meta-analysis of RCTs. Homogeneity between studies was analyzed by using I statistics. Risk ratio or mean difference of outcomes was assessed from random effects models. Subgroup analyses were conducted when necessary. Data sources are as follows: Ovid Medline, Embase, and the Cochrane Central Register of Controlled trials from inception till December 2018, bibliographies of identified reviews and trial registries for ongoing studies. RCTs comparing short-term respiratory outcomes in neonates with respiratory distress syndrome who were administered surfactant through an LMA versus standard method of care.

Results:  Six RCTs were identified, enrolling a total of 357 infants. Administering surfactant via LMA was associated with decreased FiO requirement (mean difference = 1.82 (95% confidence interval [CI]: -6.01 to 9.66), decreased intubation (risk ratio [RR] = 0.17; 95% CI: 0.05-0.57), and decreased mechanical ventilation (RR = 0.44; 95% CI: 0.31-0.61). There were no significant differences between groups for death, BPD, or pneumothorax.

Conclusion:  LMA might be an effective alternative method of surfactant delivery; however, further high-quality RCTs with larger sample size and including extreme preterm infants are needed to establish LMA as an alternative technique for surfactant delivery.

Key Points: · Pulmonary surfactants reduce mortality and pulmonary air leaks in newborns with respiratory distress syndrome.. · Preterm lungs are at risk of volutrauma by mechanical ventilation; laryngoscopy is still traumatic.. · Surfactant administration via LMA to avoid mechanical ventilation and intubation might be feasible..
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http://dx.doi.org/10.1055/s-0041-1722953DOI Listing
January 2021

Water-fat magnetic resonance imaging of adipose tissue compartments in the normal third trimester fetus.

Pediatr Radiol 2021 Jan 29. Epub 2021 Jan 29.

Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Background: Assessment of fetal adipose tissue gives information about the future metabolic health of an individual, with evidence that the development of this tissue has regional heterogeneity.

Objective: To assess differences in the proton density fat fraction (PDFF) between fetal adipose tissue compartments in the third trimester using water-fat magnetic resonance imaging (MRI).

Materials And Methods: Water-fat MRI was performed in a 1.5-T scanner. Fetal adipose tissue was segmented into cheeks, thorax, abdomen, upper arms, forearms, thighs and lower legs. PDFF and R2* values were measured in each compartment.

Results: Twenty-eight women with singleton pregnancies were imaged between 28 and 38 weeks of gestation. At 30 weeks' gestation (n=22), the PDFF was statistically different between the compartments (P<0.0001), with the highest PDFF in cheeks, followed by upper arms, thorax, thighs, forearms, lower legs and abdomen. There were no statistical differences in the rate of PDFF change with gestational age between the white adipose tissue compartments (P=0.97). Perirenal brown adipose tissue had a different PDFF and R2* compared to white adipose tissue, while the rate of R2* change did not significantly change with gestational age between white adipose tissue compartments (P=0.96).

Conclusion: Fetal adipose tissue accumulates lipids at a similar rate in all white adipose tissue compartments. PDFF variances between the compartments suggest that accumulation begins at different gestational ages, starting with cheeks, followed by extremities, trunk and abdomen. Additionally, MRI was able to detect differences in the PDFF between fetal brown adipose tissue and white adipose tissue.
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http://dx.doi.org/10.1007/s00247-020-04955-zDOI Listing
January 2021

Correlation between Medication Administration-Related Errors in Patients with Parkinson Disease and Timing of Pharmacy-Led Best Possible Medication Histories.

Can J Hosp Pharm 2021 1;74(1):15-20. Epub 2021 Jan 1.

, BScPharm, ACPR, is a Pharmacist with the Victoria Hospital, London Health Sciences Centre, London, Ontario.

Background: Poor prescribing and incomplete medication administration have been linked to increased lengths of hospitalization for patients with Parkinson disease. The Institute for Safe Medication Practices (ISMP) has recommended that patients with Parkinson disease receive a pharmacy consultation within 2 h of admission to hospital.

Objectives: To examine whether the time for a pharmacy team member to obtain a best possible medication history (BPMH) was associated with administration-related medication errors. The primary outcome was the proportion of doses with a medication error during a patient's admission in relation to the time to completion of the initial BPMH by a registered pharmacist (RPh) or registered pharmacy technician (RPhT). The secondary objective was to compare the proportion of doses with a medication error in relation to whether the BPMH was completed by an RPh or an RPhT.

Methods: This retrospective chart review involved patients with Parkinson disease who were admitted to the medicine services at London Health Sciences Centre from September 30, 2014, to September 30, 2018. Patients were included if they had Parkinson disease and a medication regimen that included levodopa-carbidopa. For all patients, an RPhT or RPh conducted the initial BPMH or updated the BPMH. Pearson correlation analysis was used to determine whether a correlation existed between administration-related errors and completion of the BPMH by a pharmacy staff member.

Results: A total of 84 patients with 104 admissions were included. There was no significant correlation between the time to completion of the initial BPMH by a pharmacy team member and the proportion of doses with medication errors ( = 0.32). Although RPhTs completed the BPMHs more quickly than RPhs ( < 0.001), there was no significant difference between pharmacy team members in terms of the proportion of doses with medication errors ( = 0.86).

Conclusions: Completing a BPMH within 2 h of a patient's admission, as per the ISMP recommendation, is unlikely to affect administration-related medication errors, given that no correlation was identified. Expediting BPMH without addressing other factors is insufficient, and initiatives are required to improve the medication administration process.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801329PMC
January 2021

Effects of a Motor Imagery Task on Functional Brain Network Community Structure in Older Adults: Data from the Brain Networks and Mobility Function (B-NET) Study.

Brain Sci 2021 Jan 17;11(1). Epub 2021 Jan 17.

Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27103, USA.

Elucidating the neural correlates of mobility is critical given the increasing population of older adults and age-associated mobility disability. In the current study, we applied graph theory to cross-sectional data to characterize functional brain networks generated from functional magnetic resonance imaging data both at rest and during a motor imagery (MI) task. Our MI task is derived from the Mobility Assessment Tool-short form (MAT-sf), which predicts performance on a 400 m walk, and the Short Physical Performance Battery (SPPB). Participants ( = 157) were from the Brain Networks and Mobility (B-NET) Study (mean age = 76.1 ± 4.3; % female = 55.4; % African American = 8.3; mean years of education = 15.7 ± 2.5). We used community structure analyses to partition functional brain networks into communities, or subnetworks, of highly interconnected regions. Global brain network community structure decreased during the MI task when compared to the resting state. We also examined the community structure of the default mode network (DMN), sensorimotor network (SMN), and the dorsal attention network (DAN) across the study population. The DMN and SMN exhibited a task-driven decline in consistency across the group when comparing the MI task to the resting state. The DAN, however, displayed an increase in consistency during the MI task. To our knowledge, this is the first study to use graph theory and network community structure to characterize the effects of a MI task, such as the MAT-sf, on overall brain network organization in older adults.
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http://dx.doi.org/10.3390/brainsci11010118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830141PMC
January 2021

Man vs. Machine: Comparing Physician vs. Electronic Health Record-Based Model Predictions for 30-Day Hospital Readmissions.

J Gen Intern Med 2021 Jan 14. Epub 2021 Jan 14.

Department of Internal Medicine, UT Southwestern, Dallas, TX, USA.

Background: Electronic health record (EHR)-based readmission risk prediction models can be automated in real-time but have modest discrimination and may be missing important readmission risk factors. Clinician predictions of readmissions may incorporate information unavailable in the EHR, but the comparative usefulness is unknown. We sought to compare clinicians versus a validated EHR-based prediction model in predicting 30-day hospital readmissions.

Methods: We conducted a prospective survey of internal medicine clinicians in an urban safety-net hospital. Clinicians prospectively predicted patients' 30-day readmission risk on 5-point Likert scales, subsequently dichotomized into low- vs. high-risk. We compared human with machine predictions using discrimination, net reclassification, and diagnostic test characteristics. Observed readmissions were ascertained from a regional hospitalization database. We also developed and assessed a "human-plus-machine" logistic regression model incorporating both human and machine predictions.

Results: We included 1183 hospitalizations from 106 clinicians, with a readmission rate of 20.8%. Both clinicians and the EHR model had similar discrimination (C-statistic 0.66 vs. 0.66, p = 0.91). Clinicians had higher specificity (79.0% vs. 48.9%, p < 0.001) but lower sensitivity (43.9 vs. 75.2%, p < 0.001) than EHR model predictions. Compared with machine, human was better at reclassifying non-readmissions (non-event NRI + 30.1%) but worse at reclassifying readmissions (event NRI - 31.3%). A human-plus-machine approach best optimized discrimination (C-statistic 0.70, 95% CI 0.67-0.74), sensitivity (65.5%), and specificity (66.7%).

Conclusion: Clinicians had similar discrimination but higher specificity and lower sensitivity than EHR model predictions. Human-plus-machine was better than either alone. Readmission risk prediction strategies should incorporate clinician assessments to optimize the accuracy of readmission predictions.
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http://dx.doi.org/10.1007/s11606-020-06355-3DOI Listing
January 2021

Mechanisms of TGFß in prostaglandin synthesis and sperm guidance in Caenorhabditis elegans.

Dev Dyn 2021 Jan 7. Epub 2021 Jan 7.

Department of Cell Development and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: The transparent epidermis of Caenorhabditis elegans makes it an attractive model to study sperm motility and migration within an intact reproductive tract. C elegans synthesize specific F-series prostaglandins (PGFs) that are important for guiding sperm toward the spermatheca. These PGFs are synthesized from polyunsaturated fatty acid (PUFA) precursors, such as arachidonic acid (AA), via a novel pathway, independent of the classical cyclooxygenases (Cox) responsible for most PG synthesis. While the enzyme(s) responsible for PG synthesis has yet to be identified, the DAF-7 TGFß pathway has been implicated in modulating PG levels and sperm guidance.

Results: We find that the reduced PGF levels in daf-1 type I receptor mutants are responsible for the sperm guidance defect. The lower level of PGs in daf-1 mutants is due in part to the inaccessibility of AA. Finally, lipid analysis and assessment of sperm guidance in daf-1;daf-3 double mutants suggest DAF-3 suppresses PG production and sperm accumulation at the spermatheca. Our data suggest that DAF-3 functions in the nervous system, and possibly the germline, to affect sperm guidance.

Conclusion: The C elegans TGFß pathway regulates many pathways to modulate PG metabolism and sperm guidance. These pathways likely function in the nervous system and possibly the germline.
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http://dx.doi.org/10.1002/dvdy.296DOI Listing
January 2021

Multimodal MRI assessment for first episode psychosis: A major change in the thalamus and an efficient stratification of a subgroup.

Hum Brain Mapp 2021 Mar 30;42(4):1034-1053. Epub 2020 Dec 30.

Department Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Multi-institutional brain imaging studies have emerged to resolve conflicting results among individual studies. However, adjusting multiple variables at the technical and cohort levels is challenging. Therefore, it is important to explore approaches that provide meaningful results from relatively small samples at institutional levels. We studied 87 first episode psychosis (FEP) patients and 62 healthy subjects by combining supervised integrated factor analysis (SIFA) with a novel pipeline for automated structure-based analysis, an efficient and comprehensive method for dimensional data reduction that our group recently established. We integrated multiple MRI features (volume, DTI indices, resting state fMRI-rsfMRI) in the whole brain of each participant in an unbiased manner. The automated structure-based analysis showed widespread DTI abnormalities in FEP and rs-fMRI differences between FEP and healthy subjects mostly centered in thalamus. The combination of multiple modalities with SIFA was more efficient than the use of single modalities to stratify a subgroup of FEP (individuals with schizophrenia or schizoaffective disorder) that had more robust deficits from the overall FEP group. The information from multiple MRI modalities and analytical methods highlighted the thalamus as significantly abnormal in FEP. This study serves as a proof-of-concept for the potential of this methodology to reveal disease underpins and to stratify populations into more homogeneous sub-groups.
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http://dx.doi.org/10.1002/hbm.25276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856640PMC
March 2021

Middle Cerebral Artery Aneurysm Clipping With Immersive 360° Virtual Reality Model: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2021 Mar;20(4):E314

Surgical Theater, Cleveland, Ohio.

This is a 50-yr-old female who presented with severe headaches and was found to have an unruptured middle cerebral artery (MCA) aneurysm. She was taken to the operating room for microsurgical clipping. Prior to surgery, an interactive 360° virtual reality (VR) model (Surgical Theatre Inc) rendered from the patient's volumetric computed tomography (CT) angiography (CTA) was used for patient education and operative planning. The aneurysm was located at the MCA trifurcation, and the VR model was used to rehearse clip options prior to surgery. A right pterional craniotomy was performed with a dissection through the sylvian fissure down the M1 segment of the MCA for proximal control. The surgical clips are placed and highlighted in the virtual platform simultaneously. Doppler and indocyanine green (ICG) confirmed patent flow through the MCA trifurcation. A postoperative angiogram confirmed no aneurysm filling. The immersive 360° VR models of pre- and postoperative CTA were shown to the patient at the 1-mo follow-up. The case presented here demonstrates the utilization of the 360° VR model for patient education, preoperative planning, and intraoperative visualization. It is imperative to remain flexible during surgery to change the strategy based on the aneurysm anatomy intraoperatively. Importantly, the interactive 360° VR model allowed for a detailed evaluation of the patient-specific anatomy prior to surgery and helped understand the complex anatomy in high resolution. The patient consented to the procedure and publication of this video for educational purposes.
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http://dx.doi.org/10.1093/ons/opaa416DOI Listing
March 2021