Publications by authors named "Timothy Miller"

359 Publications

Duke University Medical Center Perioperative Diabetes Management Program.

Clin Diabetes 2021 Apr;39(2):208-214

Duke University Medical Center, Durham, NC.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of . The following article describes a project at an academic tertiary-care medical center aimed at identifying surgical patients with uncontrolled diabetes early in the preoperative process to improve their perioperative glycemic control and surgical outcomes.
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http://dx.doi.org/10.2337/cd20-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061555PMC
April 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 May 11. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
May 2021

Normalizing Clinical Document Titles to LOINC Document Ontology: an Initial Study.

AMIA Annu Symp Proc 2020 25;2020:1441-1450. Epub 2021 Jan 25.

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.

The normalization of clinical documents is essential for health information management with the enormous amount of clinical documentation generated each year. The LOINC Document Ontology (DO) is a universal clinical document standard in a hierarchical structure. The objective of this study is to investigate the feasibility and generalizability of LOINC DO by mapping from clinical note titles across five institutions to five DO axes. We first developed an annotation framework based on the definition of LOINC DO axes and manually mapped 4,000 titles. Then we introduced a pre-trained deep learning model named Bidirectional Encoder Representations from Transformers (BERT) to enable automatic mapping from titles to LOINC DO axes. The results showed that the BERT-based automatic mapping achieved improved performance compared with the baseline model. By analyzing both manual annotations and predicted results, ambiguities in LOINC DO axes definition were discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075502PMC
January 2021

Imaging for Treated Aneurysms (Including Clipping, Coiling, Stents, Flow Diverters).

Neuroimaging Clin N Am 2021 May;31(2):251-263

Neurology and Neurosurgery, Department of Radiology, Interventional Neuroradiology, CMIT Center, University of Maryland School of Medicine, 22 S Greene Street, Baltimore, MD 21201, USA.

Intracranial aneurysms are common in the adult population and carry a risk of rupture leading to catastrophic subarachnoid hemorrhage. Treatment of aneurysms has evolved significantly, with the introduction of new techniques and devices for minimally invasive and endovascular approaches. Follow-up imaging after aneurysm treatment is standard of care to monitor for recurrence or other complications, and the preferred imaging modality and schedule for follow-up are areas of active research. The modality and follow-up schedule should be tailored to treatment technique, aneurysm characteristics, and patient factors.
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http://dx.doi.org/10.1016/j.nic.2021.01.003DOI Listing
May 2021

Assisted Fluid Management Software Guidance for Intraoperative Fluid Administration.

Anesthesiology 2021 Apr 26. Epub 2021 Apr 26.

Background: Excessive or inadequate fluid administration causes complications, but despite this, fluid administration during noncardiac surgery is highly variable. Goal-directed management helps optimize the amount and timing of fluid administration; however, implementation is difficult because algorithms are complex. The authors therefore tested the performance of the Acumen Assisted Fluid Management software (Edwards Lifesciences, USA), which is designed to guide optimal intravenous fluid administration during surgery.

Methods: In this multicenter, prospective, single-arm cohort evaluation, the authors enrolled 330 adults scheduled for moderate- to high-risk noncardiac surgery that required arterial catheter insertion and mechanical ventilation. Clinicians chose a fluid strategy based on a desired 10%, 15%, or 20% increase in stroke volume (SV) in response to a fluid bolus. Dedicated fluid management software prompted "test" or "recommended" boluses, and clinicians were free to initiate a "user" bolus of 100 to 500 ml of crystalloid or colloid. Clinicians were free to accept or decline the software prompts. The authors primarily compared the fraction of software-recommended boluses that produced suitable increases in SV to a 30% reference rate. On an exploratory basis, we compared responses to software-recommended and clinician-initiated boluses.

Results: Four hundred twenty-four of 479 (89%) software-recommended fluid boluses and 508 of 592 (86%) clinician-initiated fluid boluses were analyzed per protocol. Of those, 66% (95% CI, 62 to 70%) of delivered fluid boluses recommended by the software resulted in desired increases in SV, compared with the 30% reference rate, whereas only 41% (95% CI, 38 to 44%) of clinician-initiated boluses did (P < 0.0001). The mean ± SD increase in SV after boluses recommended by the software was 14.2 ± 13.9% versus 8.3 ± 12.1% (P < 0.0001) for those initiated by clinicians.

Conclusions: Fluid boluses recommended by the software resulted in desired SV increases more often, and with greater absolute SV increase, than clinician-initiated boluses. Automated assessment of fluid responsiveness may help clinicians optimize intraoperative fluid management during noncardiac surgery.

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http://dx.doi.org/10.1097/ALN.0000000000003790DOI Listing
April 2021

Is presymptomatic ALS perivascular?

Nat Med 2021 04;27(4):585-586

Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA.

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http://dx.doi.org/10.1038/s41591-021-01311-yDOI Listing
April 2021

Clinical Natural Language Processing for Radiation Oncology: A Review and Practical Primer.

Int J Radiat Oncol Biol Phys 2021 Feb 3. Epub 2021 Feb 3.

Computational Health Informatics Program, Boston Children's Hospital, Boston, Massachusetts.

Natural language processing (NLP), which aims to convert human language into expressions that can be analyzed by computers, is one of the most rapidly developing and widely used technologies in the field of artificial intelligence. Natural language processing algorithms convert unstructured free text data into structured data that can be extracted and analyzed at scale. In medicine, this unlocking of the rich, expressive data within clinical free text in electronic medical records will help untap the full potential of big data for research and clinical purposes. Recent major NLP algorithmic advances have significantly improved the performance of these algorithms, leading to a surge in academic and industry interest in developing tools to automate information extraction and phenotyping from clinical texts. Thus, these technologies are poised to transform medical research and alter clinical practices in the future. Radiation oncology stands to benefit from NLP algorithms if they are appropriately developed and deployed, as they may enable advances such as automated inclusion of radiation therapy details into cancer registries, discovery of novel insights about cancer care, and improved patient data curation and presentation at the point of care. However, challenges remain before the full value of NLP is realized, such as the plethora of jargon specific to radiation oncology, nonstandard nomenclature, a lack of publicly available labeled data for model development, and interoperability limitations between radiation oncology data silos. Successful development and implementation of high quality and high value NLP models for radiation oncology will require close collaboration between computer scientists and the radiation oncology community. Here, we present a primer on artificial intelligence algorithms in general and NLP algorithms in particular; provide guidance on how to assess the performance of such algorithms; review prior research on NLP algorithms for oncology; and describe future avenues for NLP in radiation oncology research and clinics.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.044DOI Listing
February 2021

Safety of the APOLLO Onyx delivery microcatheter for embolization of brain arteriovenous malformations: results from a prospective post-market study.

J Neurointerv Surg 2021 Feb 1. Epub 2021 Feb 1.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Catheter retention and difficulty in retrieval have been observed during embolization of brain arteriovenous malformations (bAVMs) with the Onyx liquid embolic system (Onyx). The Apollo Onyx delivery microcatheter (Apollo) is a single lumen catheter designed for controlled delivery of Onyx into the neurovasculature, with a detachable distal tip to aid catheter retrieval. This study evaluates the safety of the Apollo for delivery of Onyx during embolization of bAVMs.

Methods: This was a prospective, non-randomized, single-arm, multicenter, post-market study of patients with a bAVM who underwent Onyx embolization with the Apollo between May 2015 and February 2018. The primary endpoint was any catheter-related adverse event (AE) at 30 days, such as unintentional tip detachment or malfunction with clinical sequelae, or retained catheter. Procedure-related AEs (untoward medical occurrence, disease, injury, or clinical signs) and serious AEs (life threatening illness or injury, permanent physiological impairment, hospitalization, or requiring intervention) were also recorded.

Results: A total of 112 patients were enrolled (mean age 44.1±17.6 years, 56.3% men), and 201 Apollo devices were used in 142 embolization procedures. The mean Spetzler-Martin grade was 2.38. The primary endpoint was not observed (0/112, 0%). The catheter tip detached during 83 (58.5%) procedures, of which 2 (2.4%) were unintentional and did not result in clinical sequelae. At 30 days, procedure related AEs occurred in 26 (23.2%) patients, and procedure-related serious AEs in 12 (10.7%). At 12 months, there were 3 (2.7%) mortalities, including 2 (1.8%) neurological deaths, none of which were device-related.

Conclusion: This study demonstrates the safety of Apollo for Onyx embolization of bAVMs.

Clinical Trial Registration: CNCT02378883.
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http://dx.doi.org/10.1136/neurintsurg-2020-016830DOI Listing
February 2021

Deep representation learning of patient data from Electronic Health Records (EHR): A systematic review.

J Biomed Inform 2021 Mar 31;115:103671. Epub 2020 Dec 31.

School of Biomedical Informatics, The University of Texas Health Science Center at Houston, TX, USA. Electronic address:

Objectives: Patient representation learning refers to learning a dense mathematical representation of a patient that encodes meaningful information from Electronic Health Records (EHRs). This is generally performed using advanced deep learning methods. This study presents a systematic review of this field and provides both qualitative and quantitative analyses from a methodological perspective.

Methods: We identified studies developing patient representations from EHRs with deep learning methods from MEDLINE, EMBASE, Scopus, the Association for Computing Machinery (ACM) Digital Library, and the Institute of Electrical and Electronics Engineers (IEEE) Xplore Digital Library. After screening 363 articles, 49 papers were included for a comprehensive data collection.

Results: Publications developing patient representations almost doubled each year from 2015 until 2019. We noticed a typical workflow starting with feeding raw data, applying deep learning models, and ending with clinical outcome predictions as evaluations of the learned representations. Specifically, learning representations from structured EHR data was dominant (37 out of 49 studies). Recurrent Neural Networks were widely applied as the deep learning architecture (Long short-term memory: 13 studies, Gated recurrent unit: 11 studies). Learning was mainly performed in a supervised manner (30 studies) optimized with cross-entropy loss. Disease prediction was the most common application and evaluation (31 studies). Benchmark datasets were mostly unavailable (28 studies) due to privacy concerns of EHR data, and code availability was assured in 20 studies.

Discussion & Conclusion: The existing predictive models mainly focus on the prediction of single diseases, rather than considering the complex mechanisms of patients from a holistic review. We show the importance and feasibility of learning comprehensive representations of patient EHR data through a systematic review. Advances in patient representation learning techniques will be essential for powering patient-level EHR analyses. Future work will still be devoted to leveraging the richness and potential of available EHR data. Reproducibility and transparency of reported results will hopefully improve. Knowledge distillation and advanced learning techniques will be exploited to assist the capability of learning patient representation further.
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http://dx.doi.org/10.1016/j.jbi.2020.103671DOI Listing
March 2021

PD-L1+ dendritic cells in the tumor microenvironment correlate with good prognosis and CD8+ T cell infiltration in colon cancer.

Cancer Sci 2021 Mar 21;112(3):1173-1183. Epub 2021 Jan 21.

Colorectal Research Unit, St. John of God Subiaco Hospital, Subiaco, WA, Australia.

Background: The prognostic value of tumor-associated dendritic cells (DC) in colon cancer remains poorly understood. This may be in part due to the interchangeable expression of immunostimulatory and immunoinhibitory molecules on DC. Here we investigated the prognostic impact of CD11c DC co-expressing the immunoinhibitory molecule PD-L1 and their spatial relationship with CD8 T-cells in patients treated for stage III colon cancer.

Methods: Tissue microarrays containing representative cores of central tumor, leading edge, and adjacent normal tissue from 221 patients with stage III colon cancer were immunostained for CD8, CD11c, PD-L1, and cytokeratin using immunofluorescent probes. Cells were quantified using StrataQuest digital image analysis software, with intratumoral and stromal regions analyzed separately. Kaplan-Meier estimates and Cox regression were used to assess survival.

Results: Intratumoral CD8 cell density (HR = .52, 95% confidence interval [CI] .33-.83, P = .007), stromal CD11c cell density (HR = .52, 95% CI .33-.83, P = .006), intratumoral CD11c PD-L1 cell density (HR = .57, 95% CI .35-.92, P = .021), and stromal CD11c PD-L1 cell density (HR = .48, 95% CI .30-.77, P = .003) on leading-edge cores were all significantly associated with good survival. CD8 cell density was positively correlated with both CD11c cell density and CD11c PD-L1 cell density in tumor epithelium and stromal compartments.

Conclusion: Here we showed that PD-L1-expressing DC in the tumor microenvironment are associated with improved survival in stage III colon cancer and likely reflect an immunologically "hot" tumor microenvironment. Further investigation into the expression of immunomodulatory molecules by tumor-associated DC may help to further elucidate their prognostic value.
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http://dx.doi.org/10.1111/cas.14781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935795PMC
March 2021

Unplanned Emergency Visits and Admissions After Orthopaedic Ambulatory Surgery in the First 2 Years of Operation of a University Ambulatory Surgery Center.

Am J Sports Med 2021 02 17;49(2):505-511. Epub 2020 Dec 17.

Department of Orthopaedics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Ambulatory surgeries have increased in recent decades to help improve efficiency and cost; however, there is a potential need for unplanned postoperative admission, clinic visits, or evaluation in the emergency department (ED).

Purpose/hypothesis: The purpose was to determine the frequency, reasons, and factors influencing hospitalizations, return to clinic, and/or ED encounters within 24 hours of ambulatory surgery. The time frame for data collection was the first 2 years of operation of a university sports medicine ambulatory surgery center (ASC). We hypothesized that the percentage of encounters would be low and primarily because of pain or postoperative complication.

Study Design: Case-control study; Level of evidence, 3.

Methods: A retrospective review was performed of all patients undergoing ambulatory surgery at an ASC during the first 2 years of its operation (November 2016 to October 2018). Data including age, sex, Current Procedural Terminology code, procedure performed, American Society of Anesthesiologists classification, body mass index, medical history, and tobacco use were collected. Patients seeking care in the ED, inpatient, or outpatient setting within the first 24 hours after surgery were identified and the reasons for these encounters were categorized into 1 of 3 groups: (1) medical complication, (2) postoperative pain, or (3) other postoperative complication. Logistic regression models were used to assess risk factors for these encounters.

Results: A total of 4650 sports medicine procedures were performed at the university ASC during the study period. A total of 35 patients (0.75%) sought additional care within 24 hours of surgery. Medical complications were the primary reason for seeking care (n = 16; 45.7%). Patients who sought treatment within 24 hours of surgery tended to be older, had more medical comorbidities, and were more likely to have undergone upper extremity (particularly shoulder) procedures. In the multivariable analysis, patients with higher ASA scores were more likely to seek additional care ( < .005) and there was a trend toward increased risk of seeking additional care with upper extremity surgery ( = .077).

Conclusion: Orthopaedic procedures performed in an ASC result in a relatively low percentage of patients seeking additional care within the first 24 hours after surgery, consistent with other reports in the literature. Upper extremity procedures, particularly those of the shoulder, may carry an increased risk of requiring medical treatment within 24 hours of surgery. Even in the first 2 years of operation of a university-based ASC, low rates of postoperative complications and unplanned admissions can be maintained.
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http://dx.doi.org/10.1177/0363546520976626DOI Listing
February 2021

Impact of clinical photographs on the accuracy and confidence in the histopathological diagnosis of mycosis fungoides.

J Cutan Pathol 2020 Dec 16. Epub 2020 Dec 16.

Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, Washington, USA.

Background: The histopathological diagnosis of MF is challenging, and there is significant overlap with benign inflammatory processes. Clinical features may be relevant in the assessment of skin biopsies.

Methods: We provided photomicrographs to board-certified dermatopathologists and one hematopathologist with and without accompanying clinical photographs and assessed accuracy and confidence in diagnosing MF.

Results: We found that access to clinical photographs improved diagnostic accuracy in both MF and non-MF (distractors); the degree of improvement was significantly higher in the non-MF/distractor category. Across all categories, diagnostic confidence level was higher when clinical images were available.

Conclusion: These findings suggest that clinical images are useful in making an accurate diagnosis of MF, and may be particularly helpful in ruling it out when an inflammatory disorder is clinically suspected.
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http://dx.doi.org/10.1111/cup.13938DOI Listing
December 2020

Endovascular therapy in the distal neurovascular territory: results of a large prospective registry.

J Neurointerv Surg 2020 Dec 15. Epub 2020 Dec 15.

Department of Neurosciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.

Background: There is a paucity of data regarding mechanical thrombectomy (MT) in distal arterial occlusions (DAO). We aim to evaluate the safety and efficacy of MT in patients with DAO and compare their outcomes with proximal arterial occlusion (PAO) strokes.

Methods: The Trevo Registry was a prospective open-label MT registry including 2008 patients from 76 sites across 12 countries. Patients were categorized into: PAO: intracranial ICA, and MCA-M1; and DAO: MCA-M2, MCA-M3, ACA, and PCA. Baseline and outcome variables were compared across the PAO vs DAO patients with pre-morbid mRS 0-2.

Results: Among 407 DAOs including 350 (86.0%) M2, 25 (6.1%) M3, 10 (2.5%) ACA, and 22 (5.4%) PCA occlusions, there were 376 DAO with pre-morbid mRS 0-2 which were compared with 1268 PAO patients. The median baseline NIHSS score was lower in DAO (13 [8-18] vs 16 [12-20], P<0.001). There were no differences in terms of age, sex, IV-tPA use, co-morbidities, or time to treatment across DAO vs PAO. The rates of post-procedure reperfusion, symptomatic intracranial hemorrhage (sICH), and 90-mortality were comparable between both groups. DAO showed significantly higher rates of 90-day mRS 0-2 (68.3% vs 56.5%, P<0.001). After adjustment for potential confounders, the level of arterial occlusion was not associated with the chances of excellent outcome (DAO for 90-day mRS 0-1: OR; 1.18, 95% CI [0.90 to 1.54], P=0.225), successful reperfusion or SICH. However, DAO patients were more likely to be functionally independent (mRS 0-2: OR; 1.45, 95% CI [1,09 to 1.92], P=0.01) or dead (OR; 1.54, 95% CI [1.06 to 2.27], P=0.02) at 90 days.

Conclusion: Endovascular therapy in DAO appears to result in a comparable safety and technical success profile as in PAO. The potential benefits of DAO thrombectomy should be investigated in future randomized trials.
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http://dx.doi.org/10.1136/neurintsurg-2020-016851DOI Listing
December 2020

Association between perioperative fluid management and patient outcomes: a multicentre retrospective study.

Br J Anaesth 2021 Mar 13;126(3):720-729. Epub 2020 Dec 13.

Department of Critical Care Medicine, Orlando Regional Medical Center, Orlando, FL, USA. Electronic address:

Background: Postoperative complications increase hospital length of stay and patient mortality. Optimal perioperative fluid management should decrease patient complications. This study examined associations between fluid volume and noncardiac surgery patient outcomes within a large multicentre US surgical cohort.

Methods: Adults undergoing noncardiac procedures from January 1, 2012 to December 31, 2017, with a postoperative length of stay ≥24 h, were extracted from a large US electronic health record database. Patients were segmented into quintiles based on recorded perioperative fluid volumes with Quintile 3 (Q3) serving as the reference. The primary outcome was defined as a composite of any complications during the surgical admission and a postoperative length of stay ≥7 days. Secondary outcomes included in-hospital mortality, respiratory complications, and acute kidney injury.

Results: A total of 35 736 patients met the study criteria. There was a U-shaped pattern with highest (Q5) and lowest (Q1) quintiles of fluid volumes having increased odds of complications and a postoperative length of stay ≥7 days (Q5: odds ratio [OR] 1.51 [95% confidence interval {CI}: 1.30-1.74], P<0.001; Q1: OR 1.20 [95% CI: 1.04-1.38], P=0.011) compared with Q3. Patients in Q5 had greater odds of more severe acute kidney injury compared with Q3 (OR 1.52 [95% CI: 1.22-1.90]; P<0.001) and respiratory complications (OR 1.44 [95% CI: 1.17-1.77]; P<0.001).

Conclusions: Both very high and very low perioperative fluid volumes were associated with an increase in complications after noncardiac surgery.
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http://dx.doi.org/10.1016/j.bja.2020.10.031DOI Listing
March 2021

Incorporating Risk Factor Embeddings in Pre-trained Transformers Improves Sentiment Prediction in Psychiatric Discharge Summaries.

Proc Conf Empir Methods Nat Lang Process 2020 Nov;2020:35-40

Computational Health Informatics Program, Boston Children's Hospital, Boston, MA.

Reducing rates of early hospital readmission has been recognized and identified as a key to improve quality of care and reduce costs. There are a number of risk factors that have been hypothesized to be important for understanding re-admission risk, including such factors as problems with substance abuse, ability to maintain work, relations with family. In this work, we develop RoBERTa-based models to predict the sentiment of sentences describing readmission risk factors in discharge summaries of patients with psychosis. We improve substantially on previous results by a scheme that shares information across risk factors while also allowing the model to learn risk factor-specific information.
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http://dx.doi.org/10.18653/v1/2020.clinicalnlp-1.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729285PMC
November 2020

Operational Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic and Early Recovery Trends: University of Washington Anatomic Pathology Experience.

Arch Pathol Lab Med 2021 04;145(4):399-406

From the Department of Laboratory Medicine and Pathology (Miller, Smith, Swanson), University of Washington, Seattle.

Context.—: The coronavirus disease 2019 pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, has resulted in worldwide disruption to the delivery of patient care. The Seattle, Washington metropolitan area was one of the first in the United States affected by the pandemic. As a result, the anatomic pathology services at the University of Washington experienced significant changes in operational volumes early in the pandemic.

Objective.—: To assess the impact of coronavirus disease 2019 and both state and institutional policies implemented to mitigate viral transmission (including institutional policies on nonurgent procedures) on anatomic pathology volumes.

Design.—: Accessioned specimens from January to June 2020 were evaluated as coronavirus disease 2019 and institutional policies changed. The data were considered in these contexts: subspecialty, billable Current Procedural Terminology codes, and intraoperative consultation. Comparable data were retrieved from 2019 as a historical control.

Results.—: There was a significant reduction in overall accessioned volume (up to 79%) from prepandemic levels during bans on nonurgent procedures when compared with 2020 pre-coronavirus disease 2019 volumes and historical controls. The gastrointestinal and dermatopathology services were most impacted, and breast and combined head and neck/pulmonary services were least impacted. Current Procedural Terminology code 88305, for smaller/biopsy specimens, had a 63% reduction during nonurgent procedure bans. After all bans on procedures were lifted, the overall volume plateaued at 89% of prepandemic levels.

Conclusions.—: A significant decrease in specimen volume was most strongly associated with bans on nonurgent procedures. Although all departmental areas had a decrease in volume, the extent of change varied across subspecialty and specimen types. Even with removal of all bans, service volume did not reach prepandemic levels.
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http://dx.doi.org/10.5858/arpa.2020-0639-SADOI Listing
April 2021

Pre-training phenotyping classifiers.

J Biomed Inform 2021 Jan 28;113:103626. Epub 2020 Nov 28.

Computational Health Informatics Program (CHIP), Boston Children's Hospital and Harvard Medical School, Boston, MA, United States. Electronic address:

Recent transformer-based pre-trained language models have become a de facto standard for many text classification tasks. Nevertheless, their utility in the clinical domain, where classification is often performed at encounter or patient level, is still uncertain due to the limitation on the maximum length of input. In this work, we introduce a self-supervised method for pre-training that relies on a masked token objective and is free from the limitation on the maximum input length. We compare the proposed method with supervised pre-training that uses billing codes as a source of supervision. We evaluate the proposed method on one publicly-available and three in-house datasets using the standard evaluation metrics such as the area under the ROC curve and F1 score. We find that, surprisingly, even though self-supervised pre-training performs slightly worse than supervised, it still preserves most of the gains from pre-training.
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http://dx.doi.org/10.1016/j.jbi.2020.103626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856089PMC
January 2021

Updates and Advances in the Management of Lateral Meniscal Radial Tears: A Critical Analysis Review.

JBJS Rev 2020 11;8(11):e2000056

Department of Orthopaedics, Wexner Medical Center, The Ohio State University, Columbus, Ohio.

Because of their increased mobility, lack of resistance to hoop stresses, and decreased blood supply, radial tears of the lateral meniscus are more troublesome to heal than vertical longitudinal tears. Given the success of meniscal root repairs, radial tears of the lateral meniscal body should be given strong consideration for repair because of a more reproducible ability to heal such lesions in young, active patients. Technique options that should be considered for the less common anterior radial tears of the lateral meniscus include outside-in repair, self-capturing suture-passing devices, and orthobiologic treatments to stimulate healing. Although a variety of suture techniques, including the double horizontal mattress and horizontal butterfly patterns, have demonstrated improvements in patient outcomes, evidence is still limited with regard to the ideal suture pattern for radial tears.
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http://dx.doi.org/10.2106/JBJS.RVW.20.00056DOI Listing
November 2020

Plasma neurofilament light predicts mortality in patients with stroke.

Sci Transl Med 2020 11;12(569)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Given the heterogeneity of stroke brain injury, there is a clear need for a biomarker that determines the degree of neuroaxonal injury across stroke types. We evaluated whether blood neurofilament light (NFL) would fulfill this purpose for patients with acute cerebral infarction (ACI; = 227), aneurysmal subarachnoid hemorrhage (aSAH; = 58), or nontraumatic intracerebral hemorrhage (ICH; = 29). We additionally validated our findings in two independent cohorts of patients with ICH ( = 96 and = 54) given the scarcity of blood biomarker studies for this deadliest stroke type. Compared to healthy individuals ( = 79 and = 48 for the discovery and validation cohorts, respectively), NFL was higher for all stroke types. NFL associated with radiographic markers of brain tissue damage. It correlated with the extent of early ischemic injury in patients with ACI, hemorrhage severity in patients with aSAH, and intracranial hemorrhage volume in patients with ICH. In all patients, NFL independently correlated with scores from the NIH Stroke Scale, the modified Rankin Scale, and the Mini-Mental State Examination at blood draw, which respectively assess neurological, functional, and cognitive status. Furthermore, higher NFL concentrations independently associated with 3- or 6-month functional disability and higher all-cause mortality. These data support NFL as a uniform method to estimate neuroaxonal injury and forecast mortality regardless of stroke mechanism. As a prognostic biomarker, blood NFL has the potential to assist with planning supportive and rehabilitation services and improving clinical trial efficiency for stroke therapeutics and devices.
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http://dx.doi.org/10.1126/scitranslmed.aay1913DOI Listing
November 2020

Classifying Electronic Consults for Triage Status and Question Type.

Proc Conf Assoc Comput Linguist Meet 2020 Jul;2020:1-6

Boston Children's Hospital, Boston, MA.

Electronic consult (eConsult) systems allow specialists more flexibility to respond to referrals more efficiently, thereby increasing access in under-resourced healthcare settings like safety net systems. Understanding the usage patterns of eConsult system is an important part of improving specialist efficiency. In this work, we develop and apply classifiers to a dataset of eConsult questions from primary care providers to specialists, classifying the messages for how they were triaged by the specialist office, and the underlying type of clinical question posed by the primary care provider. We show that pre-trained transformer models are strong baselines, with improving performance from domain-specific training and shared representations.
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http://dx.doi.org/10.18653/v1/2020.nlpmc-1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603636PMC
July 2020

XAI-Explainable artificial intelligence.

Sci Robot 2019 Dec;4(37)

Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai, China.

Explainability is essential for users to effectively understand, trust, and manage powerful artificial intelligence applications.
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http://dx.doi.org/10.1126/scirobotics.aay7120DOI Listing
December 2019

Smartphone data during the COVID-19 pandemic can quantify behavioral changes in people with ALS.

Muscle Nerve 2021 02 28;63(2):258-262. Epub 2020 Nov 28.

Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA.

Introduction: Passive data from smartphone sensors may be useful for health-care research. Our aim was to use the coronavirus disease-2019 (COVID-19) pandemic as a positive control to assess the ability to quantify behavioral changes in people with amyotrophic lateral sclerosis (ALS) from smartphone data.

Methods: Eight participants used the Beiwe smartphone application, which passively measured their location during the COVID-19 outbreak. We used an interrupted time series to quantify the effect of the US state of emergency declaration on daily home time and daily distance traveled.

Results: After the state of emergency declaration, median daily home time increased from 19.4 (interquartile range [IQR], 15.4-22.0) hours to 23.7 (IQR, 22.2-24.0) hours and median distance traveled decreased from 42 (IQR, 13-83) km to 3.7 (IQR, 1.5-10.3) km. The participant with the lowest functional ability changed behavior earlier. This participant stayed at home more and traveled less than the participant with highest functional ability, both before and after the state of emergency.

Discussion: We provide evidence that smartphone-based digital phenotyping can quantify the behavior of people with ALS. Although participants spent large amounts of time at home at baseline, the COVID-19 state of emergency declaration reduced their mobility further. Given participants' high level of daily home time, it is possible that their exposure to COVID-19 could be less than that of the general population.
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http://dx.doi.org/10.1002/mus.27110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898508PMC
February 2021

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on the Role of Neuromonitoring in Perioperative Outcomes: Cerebral Near-Infrared Spectroscopy.

Anesth Analg 2020 11;131(5):1444-1455

Departments of Anesthesiology and Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Some neurological complications following surgery have been related to a mismatch in cerebral oxygen supply and demand that may either lead to more subtle changes of brain function or overt complications like stroke or coma. Discovery of a perioperative neurological complication may be outside the treatment window, thereby making prevention an important focus. Early commercial devices used differential spectroscopy to measure relative changes from baseline of 2 chromophores: oxy- and deoxyhemoglobin. It was the introduction of spatially resolved spectroscopy techniques that allowed near-infrared spectroscopy (NIRS)-based cerebral oximetry as we know it today. Modern cerebral oximeters measure the hemoglobin saturation of blood in a specific "optical field" containing arterial, capillary, and venous blood, not tissue oxygenation itself. Multiple cerebral oximeters are commercially available, all of which have technical differences that make them noninterchangeable. The mechanism and meaning of these measurements are likely not widely understood by many practicing physicians. Additionally, as with many clinically used monitors, there is a lack of high-quality evidence on which clinicians can base decisions in their effort to use cerebral oximetry to reduce neurocognitive complications after surgery. Therefore, the Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together an international team of multidisciplinary experts including anesthesiologists, surgeons, and critical care physicians to objectively survey the literature on cerebral oximetry and provide consensus, evidence-based recommendations for its use in accordance with the GRading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria for evaluating biomedical literature. The group produced the following consensus recommendations: (1) interpreting perioperative cerebral oximetry measurements in the context of a preinduction baseline value; (2) interpreting perioperative cerebral oximetry measurements in the context of the physiologic variables that affect them; (3) using caution in comparing cerebral oximetry values between different manufacturers; (4) using preoperative cerebral oximetry to identify patients at increased risk of adverse outcomes after cardiac surgery; (5) using intraoperative cerebral oximetry indexed to preinduction baseline to identify patients at increased risk of adverse outcomes after cardiac surgery; (6) using cerebral oximetry to identify and guide management of acute cerebral malperfusion during cardiac surgery; (7) using an intraoperative cerebral oximetry-guided interventional algorithm to reduce intensive care unit (ICU) length of stay after cardiac surgery. Additionally, there was agreement that (8) there is insufficient evidence to recommend using intraoperative cerebral oximetry to reduce mortality or organ-specific morbidity after cardiac surgery; (9) there is insufficient evidence to recommend using intraoperative cerebral oximetry to improve outcomes after noncardiac surgery.
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http://dx.doi.org/10.1213/ANE.0000000000005081DOI Listing
November 2020

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.

Elife 2020 10 19;9. Epub 2020 Oct 19.

Department of Internal Medicine, Pharmacogenomics, Washington University School of Medicine, St Louis, United States.

Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal mutation. In mice expressing human T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.
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http://dx.doi.org/10.7554/eLife.61119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655101PMC
October 2020

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 30;63(1):31-39. Epub 2020 Oct 30.

Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
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http://dx.doi.org/10.1002/mus.27091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820979PMC
January 2021

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of In Patients With ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 24;22(3-4):287-299. Epub 2020 Sep 24.

Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.

Objective: To evaluate safety, dose response, and preliminary efficacy of over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Patients ( = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,  = 0.09; muscle strength mega-score,  = 0.31). Post hoc analyses pooling all active -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
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http://dx.doi.org/10.1080/21678421.2020.1822410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117790PMC
May 2021

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

N Engl J Med 2020 09;383(10):919-930

From the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School (S.P., J.D.B., S.B., M.C., D.D., M.M., J.O., L.P., A.V.S., E.T., P.V., J. Walker, H.Y., R.E.T., M.E.C.), the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School (E.A.M., J. Chan, D.S.), and Spaulding Rehabilitation Hospital, Harvard Medical School (S.P.), Boston, the University of Massachusetts Memorial Medical Center, Worcester (M.A.O.), and Amylyx Pharmaceuticals (J. Cohen, J. Klee, K.L., P.D.Y.) and Harvard University (W.G.), Cambridge - all in Massachusetts; Pentara, Millcreek, UT (S.H., S.P.D., N.E., K.H.); Swedish Neuroscience Institute, Seattle (M.A.E.); Hennepin Healthcare, Minneapolis (S.M.); the Department of Neurology, Oregon Health and Science University, Portland (C.K.); the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (J.B.C.); the Department of Neurology, Ohio State University College of Medicine, Columbus (A.Q.); the Department of Neurology, University of Florida College of Medicine, Gainesville (J. Wymer); the Department of Neurology, University of Michigan, Ann Arbor (S.A.G.); Texas Neurology, Dallas (D.H.); the Department of Neurology, Lewis Katz School of Medicine, Temple University (T.H.-P.), and the Department of Neurology, University of Pennsylvania Perelman School of Medicine (C.Q.) - both in Philadelphia; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disease, University of Texas Health Science Center at San Antonio, San Antonio (C.E.J.); the Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore (J.D.R.); the Department of Neurology, University of Kentucky College of Medicine, Lexington (E.J.K.); California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco (J. Katz, L.J.); Barrow Neurological Institute, Phoenix, AZ (S.L., M.H., G.K., R.R., J.M.S.); the Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis (T.M.M.); the Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York (S.N.S.); the Department of Neurology, University of South Florida Morsani College of Medicine, Tampa (T.H.V.); the Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta (C.N.F., J.D.G.); Ochsner Health System, New Orleans (K.M.J.); the Department of Neurology, University of Iowa Carver College of Medicine, Iowa City (A.S.); the Department of Neurology, University of California, Irvine, School of Medicine, Irvine (N.A.G.); Neurology Associates, Lincoln, NB (G.L.P.); independent consultant, Nobleboro, ME (P.L.A.); and Statistics Collaborative, Washington, DC (J. Wittes).

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.

Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.

Results: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.

Conclusions: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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http://dx.doi.org/10.1056/NEJMoa1916945DOI Listing
September 2020

Experiences implementing scalable, containerized, cloud-based NLP for extracting biobank participant phenotypes at scale.

JAMIA Open 2020 Jul 22;3(2):185-189. Epub 2020 May 22.

Computational Health Informatics Program, Boston Children's Hospital, Boston, Massachusetts, USA.

Objective: To develop scalable natural language processing (NLP) infrastructure for processing the free text in electronic health records (EHRs).

Materials And Methods: We extend the open-source Apache cTAKES NLP software with several standard technologies for scalability. We remove processing bottlenecks by monitoring component queue size. We process EHR free text for patients in the PrecisionLink Biobank at Boston Children's Hospital. The extracted concepts are made searchable via a web-based portal.

Results: We processed over 1.2 million notes for over 8000 patients, extracting 154 million concepts. Our largest tested configuration processes over 1 million notes per day.

Discussion: The unique information represented by extracted NLP concepts has great potential to provide a more complete picture of patient status.

Conclusion: NLP large EHR document collections can be done efficiently, in service of high throughput phenotyping.
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http://dx.doi.org/10.1093/jamiaopen/ooaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382623PMC
July 2020