Publications by authors named "Michael Wang"

1,226 Publications

  • Page 1 of 1

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

Haemophilia 2021 Oct 11. Epub 2021 Oct 11.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.

Introduction: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date.

Aim: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care.

Methods: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses.

Results: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee.

Conclusion: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
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http://dx.doi.org/10.1111/hae.14419DOI Listing
October 2021

Classifying Patients Operated for Spondylolisthesis: A K-Means Clustering Analysis of Clinical Presentation Phenotypes.

Neurosurgery 2021 Oct 11. Epub 2021 Oct 11.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: Trials of lumbar spondylolisthesis are difficult to compare because of the heterogeneity in the populations studied.

Objective: This study aims to define patterns of clinical presentation.

Methods: This is a study of the prospective Quality Outcomes Database spondylolisthesis registry, including patients who underwent single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Twenty-four-month patient-reported outcomes (PROs) were collected. A k-means clustering analysis-an unsupervised machine learning algorithm-was used to identify clinical presentation phenotypes.

Results: Overall, 608 patients were identified, of which 507 (83.4%) had 24-mo follow-up. Clustering revealed 2 distinct cohorts. Cluster 1 (high disease burden) was younger, had higher body mass index (BMI) and American Society of Anesthesiologist (ASA) grades, and globally worse baseline PROs. Cluster 2 (intermediate disease burden) was older and had lower BMI and ASA grades, and intermediate baseline PROs. Baseline radiographic parameters were similar (P > .05). Both clusters improved clinically (P < .001 all 24-mo PROs). In multivariable adjusted analyses, mean 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale Back Pain (NRS-BP), Numeric Rating Scale Leg Pain, and EuroQol-5D (EQ-5D) were markedly worse for the high-disease-burden cluster (adjusted-P < .001). However, the high-disease-burden cluster demonstrated greater 24-mo improvements for ODI, NRS-BP, and EQ-5D (adjusted-P < .05) and a higher proportion reaching ODI minimal clinically important difference (MCID) (adjusted-P = .001). High-disease-burden cluster had lower satisfaction (adjusted-P = .02).

Conclusion: We define 2 distinct phenotypes-those with high vs intermediate disease burden-operated for lumbar spondylolisthesis. Those with high disease burden were less satisfied, had a lower quality of life, and more disability, more back pain, and more leg pain than those with intermediate disease burden, but had greater magnitudes of improvement in disability, back pain, quality of life, and more often reached ODI MCID.
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http://dx.doi.org/10.1093/neuros/nyab355DOI Listing
October 2021

Augmented Reality Assisted Endoscopic Transforaminal Lumbar Interbody Fusion: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2021 Oct 8. Epub 2021 Oct 8.

Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Augmented reality (AR) is a novel technology for spine navigation. This tracking camera-integrated head-mounted display (HMD) represents a novel stereotactic computer navigation modality that has demonstrated excellent precision and accuracy with spinal instrumentation.1 Standard computer-assisted spine navigation systems have two major shortcomings: attention shift and line-of-sight limitations. The HMD allows visualization of the surgical field and navigation data concurrently in the same field of view.2,3 However, the use of AR in spine surgery has been limited to use for instrumentation, not for endoscopy.  Fully endoscopic transforaminal interbody fusion under conscious sedation is an effective treatment option for degenerative spondylolisthesis and spinal stenosis. Although this technique has a steep learning curve, the advantages are vast, including preservation of normal tissue, smaller incisional requirement, and reduced postoperative pain, all enabling rapid recovery after surgery. As with other endoscopic spine surgeries, this procedure has a steep learning curve and requires a robust understanding of foraminal anatomy in order to safely access the disc space.4,5 However, with the introduction of AR, the safety and precision of this procedure could be greatly improved upon.  In this video, we present a case of a 60-yr-old female who presented with a grade 1 spondylolisthesis and severe spinal stenosis and was treated with an L4-L5 interbody fusion. All instrumentation steps and localization for the endoscopic portion of the case were performed with assistance from the AR-HMD system. Informed written consent was obtained from the patient. The participant and any identifiable individuals consented to the publication of his/her image.
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http://dx.doi.org/10.1093/ons/opab346DOI Listing
October 2021

Using smartphone-based accelerometers to gauge postoperative outcomes in patients with NPH: Implications for ambulatory monitoring.

Surg Neurol Int 2021 13;12:464. Epub 2021 Sep 13.

Department of Neurological Surgery, University of Miami, Miami, Florida, United States.

Background: The surgical treatment of normal pressure hydrocephalus (NPH) with shunting remains controversial due to the difficulty in distinguishing such pathology from other neurological conditions that can present similarly. Thus, patients with suspected NPH should be carefully selected for surgical intervention. Historically, clinical improvement has been measured by the use of functional grades, alleviation of symptoms, and/or patient/family-member reported surveys. Such outcome analysis can be subjective, and there is difficulty in quantifying cognition. Thus, a push for a more quantifiable and objective investigation is warranted, especially for patients with idiopathic NPH (INPH), for which the final diagnosis is confirmed with postoperative clinical improvement. We aimed to use Apple Health (Apple Inc., Cupertino, CA) data to approximate physical activity levels before and after shunt placement for NPH as an objective outcome measurement. The patients were contacted and verbally consented to export Apple Health activity data. The patient's physical activity data were then analyzed. A chart review from the patient's EMR was performed to understand and better correlate recovery.

Case Description: Our first patient had short-term improvements in activity levels when compared to his preoperative activity. The patient's activity level subsequently decreased at 6 months and onward. This decline was simultaneous to new-onset lumbar pain. Our second patient experienced sustained improvements in activity levels for 12 months after his operation. His mobility data were in congruence with his subjectively reported improvement in clinical symptoms. He subsequently experienced a late-decline that began at 48-months. His late deterioration was likely confounded by exogenous factors such as further neurodegenerative diseases coupled with old age.

Conclusion: The use of objective activity data offers a number of key benefits in the analysis of shunted patients with NPH/INPH. In this distinctive patient population, detailed functional outcome analysis is imperative because the long-term prognosis can be affected by comorbid factors or life expectancy. The benefits from using smartphone-based accelerometers for objective outcome metrics are abundant and such an application can serve as a clinical aid to better optimize surgical and recovery care.
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http://dx.doi.org/10.25259/SNI_112_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492411PMC
September 2021

Multidimensional Tactile Sensor with a Thin Compound Eye-Inspired Imaging System.

Soft Robot 2021 Oct 7. Epub 2021 Oct 7.

Department of Mechanical and Aerospace Engineering and Hong Kong University of Science and Technology, Hong Kong, Hong Kong.

Artificial tactile sensing for robots is a counterpart to the human sense of touch, serving as a feedback interface for sensing and interacting with the environment. A vision-based tactile sensor has emerged as a novel and advantageous branch of artificial tactile sensors. Compared with conventional tactile sensors, vision-based tactile sensors possess stronger potential thanks to acquiring multimodal contact information in much higher spatial resolution, although they typically suffer from bulky size and fabrication challenges. In this article, we report a thin vision-based tactile sensor that draws inspiration from natural compound eye structures and demonstrate its capability of sensing three-dimensional (3D) force. The sensor is composed of an array of vision units, an elastic touching interface, and a supporting structure with illumination. Experiments validated the sensor's advantages, including competitive spatial resolution of deformation as high as 1016 dpi on a 5 × 8 mm sensing area, superior accuracy of 3D force measurement at levels of 0.018 N for tangential force and 0.213 N (0.108 N at the center region) for normal force, and real-time processing at 30 Hz, while achieving a thin size of 5 mm. We further demonstrate the sensor capability in sensing 3D force and slip occurrence in real grasping experiments. This device paves the way for robotic applications that require rich tactile information with miniaturized sensor structure.
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http://dx.doi.org/10.1089/soro.2020.0202DOI Listing
October 2021

Prognostic Factors for Dry Eye Disease Treatment Response in Clinical Trials.

JAMA Ophthalmol 2021 Oct 7. Epub 2021 Oct 7.

Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1001/jamaophthalmol.2021.3946DOI Listing
October 2021

Tethered tracer in a mixture of hot and cold Brownian particles: can activity pacify fluctuations?

Soft Matter 2021 Oct 7. Epub 2021 Oct 7.

Department of Physics and Center for Soft Matter Research, New York University, 726 Broadway, New York, NY 10003, USA.

We study how an interacting mixture of components with differing levels of activity can affect the fluctuations of an embedded object such as a tracer. In particular, we consider a simple model of a tracer that is harmonically bound within a mixture of hot and cold Brownian particles, which, like a mixture of active and passive particles, can phase separate. By measuring the fluctuations of the tracer, we find that this collective behavior gives rise to an effective temperature for the tracer. Additionally, we find that there is an increased tendency for cold particles to accumulate on the surface of the tracer due to the hot particles, potentially dampening its fluctuations and decreasing its effective temperature. These results suggest that the phase separation of a mixture of hot/cold or active/passive particles may have strong effects on the fluctuations of an embedded object. We discuss potential implications of these results for experiments on fluctuations of nuclear envelope affected by the activity in the chromatin.
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http://dx.doi.org/10.1039/d1sm01163dDOI Listing
October 2021

PERSEPT 3: A phase 3 clinical trial to evaluate the haemostatic efficacy of eptacog beta (recombinant human FVIIa) in perioperative care in subjects with haemophilia A or B with inhibitors.

Haemophilia 2021 Oct 6. Epub 2021 Oct 6.

Cliniques Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Introduction: Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses.

Aim: To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3.

Methods: Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period.

Results: Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported.

Conclusion: Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.
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http://dx.doi.org/10.1111/hae.14418DOI Listing
October 2021

The role of an anterior approach in the treatment of ankylosing spondylitis-associated cervical fractures: a systematic review and meta-analysis.

Neurosurg Focus 2021 10;51(4):E9

Objective: Cervical fractures in patients with ankylosing spondylitis can have devastating neurological consequences. Currently, several surgical approaches are commonly used to treat these fractures: anterior, posterior, and anterior-posterior. The relative rarity of these fractures has limited the ability of surgeons to objectively determine the merits of each. The authors present an updated systematic review and meta-analysis investigating the utility of anterior surgical approaches relative to posterior and anterior-posterior approaches.

Methods: After a comprehensive literature search of the PubMed, Cochrane, and Embase databases, 7 clinical studies were included in the final qualitative and 6 in the final quantitative analyses. Of these studies, 6 compared anterior approaches with anterior-posterior and posterior approaches, while 1 investigated only an anterior approach. Odds ratios and 95% confidence intervals were calculated where appropriate.

Results: A meta-analysis of postoperative neurological improvement revealed no statistically significant differences in gross rates of neurological improvement between anterior and posterior approaches (OR 0.40, 95% CI 0.10-1.59; p = 0.19). However, when analyzing the mean change in neurological function, patients who underwent anterior approaches had a significantly lower mean change in postoperative neurological function relative to patients who underwent posterior approaches (mean difference [MD] -0.60, 95% CI -0.76 to -0.45; p < 0.00001). An identical trend was seen between anterior and anterior-posterior approaches; there were no statistically significant differences in gross rates of neurological improvement (OR 3.05, 95% CI 0.84-11.15; p = 0.09). However, patients who underwent anterior approaches experienced a lower mean change in neurological function relative to anterior-posterior approaches (MD -0.46, 95% CI -0.60 to -0.32; p < 0.00001). There were no significant differences in complication rates between anterior approaches, posterior approaches, or anterior-posterior approaches, although complication rates trended lower in patients who underwent anterior approaches.

Conclusions: The results of this review and meta-analysis demonstrated the varying benefits of anterior approaches relative to posterior and anterior-posterior approaches in treatment of cervical fractures associated with ankylosing spondylitis. While reports demonstrated lower degrees of neurological improvement in anterior approaches, they may benefit patients with less-severe injuries if lower complication rates are desired.
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http://dx.doi.org/10.3171/2021.7.FOCUS21333DOI Listing
October 2021

Introduction. Ankylosing spondylitis.

Neurosurg Focus 2021 10;51(4):E1

6Department of Neurosurgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Germany.

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http://dx.doi.org/10.3171/2021.7.FOCUS21437DOI Listing
October 2021

Documentation and review of social determinants of health data in the EHR: measures and associated insights.

J Am Med Inform Assoc 2021 Sep 21. Epub 2021 Sep 21.

Center for Clinical Informatics & Improvement Research, University of California, San Francisco, San Francisco, California, USA.

Objective: Electronic Health Records (EHRs) increasingly include designated fields to capture social determinants of health (SDOH). We developed measures to characterize their use, and use of other SDOH data types, to optimize SDOH data integration.

Materials And Methods: We developed 3 measures that accommodate different EHR data types on an encounter or patient-year basis. We implemented these measures-documented during encounter (DDE) captures documentation occurring during the encounter; documented by discharge (DBD) includes DDE plus documentation occurring any time prior to admission; and reviewed during encounter (RDE) captures whether anyone reviewed documented data-for the newly available structured SDOH fields and 4 other comparator SDOH data types (problem list, inpatient nursing question, social history free text, and social work notes) on a hospital encounter basis (with patient-year metrics in the Supplementary Appendix). Our sample included all patients (n = 27 127) with at least one hospitalization at UCSF Health (a large, urban, tertiary medical center) over a 1-year period.

Results: We observed substantial variation in the use of different SDOH EHR data types. Notably, social history question fields (newly added at study period start) were rarely used (DDE: 0.03% of encounters, DBD: 0.26%, RDE: 0.03%). Free-text patient social history fields had higher use (DDE: 12.1%, DBD: 49.0%, RDE: 14.4%).

Discussion: Our measures of real-world SDOH data use can guide current efforts to capture and leverage these data. For our institution, measures revealed substantial variation across data types, suggesting the need to engage in efforts such as EHR-user education and targeted workflow integration.

Conclusion: Measures revealed opportunities to optimize SDOH data documentation and review.
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http://dx.doi.org/10.1093/jamia/ocab194DOI Listing
September 2021

Does reduction of the Meyerding grade correlate with outcomes in patients undergoing decompression and fusion for grade I degenerative lumbar spondylolisthesis?

J Neurosurg Spine 2021 Sep 17:1-8. Epub 2021 Sep 17.

1Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Objective: Reduction of Meyerding grade is often performed during fusion for spondylolisthesis. Although radiographic appearance may improve, correlation with patient-reported outcomes (PROs) is rarely reported. In this study, the authors' aim was to assess the impact of spondylolisthesis reduction on 24-month PRO measures after decompression and fusion surgery for Meyerding grade I degenerative lumbar spondylolisthesis.

Methods: The Quality Outcomes Database (QOD) was queried for patients undergoing posterior lumbar fusion for spondylolisthesis with a minimum 24-month follow-up, and quantitative correlation between Meyerding slippage reduction and PROs was performed. Baseline and 24-month PROs, including the Oswestry Disability Index (ODI), EQ-5D, Numeric Rating Scale (NRS)-back pain (NRS-BP), NRS-leg pain (NRS-LP), and satisfaction (North American Spine Society patient satisfaction questionnaire) scores were noted. Multivariable regression models were fitted for 24-month PROs and complications after adjusting for an array of preoperative and surgical variables. Data were analyzed for magnitude of slippage reduction and correlated with PROs. Patients were divided into two groups: < 3 mm reduction and ≥ 3 mm reduction.

Results: Of 608 patients from 12 participating sites, 206 patients with complete data were identified in the QOD and included in this study. Baseline patient demographics, comorbidities, and clinical characteristics were similarly distributed between the cohorts except for depression, listhesis magnitude, and the proportion with dynamic listhesis (which were accounted for in the multivariable analysis). One hundred four (50.5%) patients underwent lumbar decompression and fusion with slippage reduction ≥ 3 mm (mean 5.19, range 3 to 11), and 102 (49.5%) patients underwent lumbar decompression and fusion with slippage reduction < 3 mm (mean 0.41, range 2 to -2). Patients in both groups (slippage reduction ≥ 3 mm, and slippage reduction < 3 mm) reported significant improvement in all primary patient reported outcomes (all p < 0.001). There was no significant difference with regard to the PROs between patients with or without intraoperative reduction of listhesis on univariate and multivariable analyses (ODI, EQ-5D, NRS-BP, NRS-LP, or satisfaction). There was no significant difference in complications between cohorts.

Conclusions: Significant improvement was found in terms of all PROs in patients undergoing decompression and fusion for lumbar spondylolisthesis. There was no correlation with clinical outcomes and magnitude of Meyerding slippage reduction.
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http://dx.doi.org/10.3171/2021.3.SPINE202059DOI Listing
September 2021

Incidence and Clinical Outcomes of Hypothyroidism in Patients Undergoing Spinal Fusion.

Cureus 2021 Aug 11;13(8):e17099. Epub 2021 Aug 11.

Neurological Surgery, University of Miami Miller School of Medicine, Miami, USA.

Background Hypothyroidism has been independently associated with the development of several comorbidities and is known to increase complication rates in non-spinal surgeries. However, there are limited data regarding the effects of hypothyroidism in major spine surgery. Therefore, we present the largest retrospective analysis evaluating outcomes in hypothyroid patients undergoing spinal fusion. Methods A retrospective review of the National Inpatient Sample (NIS) from 2004-2014 was performed. Patients with an International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) procedure code indicating spinal fusion (81.04-81.08, 81.34-81.38, 81.0x, 81.3x) were included. Patients with an ICD-9-CM diagnosis code indicating hypothyroidism (244.x) were compared to those without. Cervical and lumbar fusions were evaluated independently. Significant covariates in univariable logistic regression were utilized to construct multivariable models to analyze the effect of hypothyroidism on perioperative morbidity and mortality. Results A total of 4,149,125 patients were identified, of which 9.4% were hypothyroid. Although, hypothyroid patients had a higher risk of hematologic complications (lumbar - odds ratio [OR] 1.176, p < 0.0001; cervical - OR 1.162, p < 0.0001), they exhibited decreased in-hospital mortality (lumbar - OR .643, p < 0.0001; cervical - OR .606, p < 0.0001). Hypothyroid lumbar fusion patients also demonstrated decreased rates of perioperative myocardial infarction (MI) (OR .851, p < 0.0001). All these results were independent of patient gender. Conclusions Hypothyroid patients undergoing spinal fusion demonstrated lower rates of inpatient mortality and, in lumbar fusions, also had lower rates of acute MI when compared to their euthyroid counterparts. This suggests that hypothyroidism may offer protection against all-cause mortality and may be cardioprotective in the postoperative period for lumbar spinal fusions independent of patient gender.
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http://dx.doi.org/10.7759/cureus.17099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432424PMC
August 2021

Computer-aided detection of mantle cell lymphoma on F-FDG PET/CT using a deep learning convolutional neural network.

Am J Nucl Med Mol Imaging 2021 15;11(4):260-270. Epub 2021 Aug 15.

Department of Imaging Physics, The University of Texas MD Anderson Cancer Center Houston, TX, USA.

F-FDG PET/CT can provide quantitative characterization with prognostic value for mantle cell lymphoma (MCL). However, detection of MCL is performed manually, which is labor intensive and not a part of the routine clinical practice. This study investigates a deep learning convolutional neural network (DLCNN) for computer-aided detection of MCL on F-FDG PET/CT. We retrospectively analyzed 142 baseline F-FDG PET/CT scans of biopsy-confirmed MCL acquired between May 2007 and October 2018. Of the 142 scans, 110 were from our institution and 32 were from outside institutions. An Xception-based U-Net was constructed to classify each pixel of the PET/CT images as MCL or not. The network was first trained and tested on the within-institution scans by applying five-fold cross-validation. Sensitivity and false positives (FPs) per patient were calculated for network evaluation. The network was then tested on the outside-institution scans, which were excluded from network training. For the 110 within-institution patients (85 male; median age, 58 [range: 39-84] years), the network achieved an overall median sensitivity of 88% (interquartile range [IQR]: 25%) with 15 (IQR: 12) FPs/patient. Sensitivity was dependent on lesion size and SUV but not on lesion location. For the 32 outside-institution patients (24 male; median age, 59 [range: 40-67] years), the network achieved a median sensitivity of 84% (IQR: 24%) with 14 (IQR: 10) FPs/patient. No significant performance difference was found between the within and outside institution scans. Therefore, DLCNN can potentially help with MCL detection on F-FDG PET/CT with high sensitivity and limited FPs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414404PMC
August 2021

Age at Diagnosis of Diabetes by Race and Ethnicity in the United States From 2011 to 2018.

JAMA Intern Med 2021 Sep 7. Epub 2021 Sep 7.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1001/jamainternmed.2021.4945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424523PMC
September 2021

The antibody drug conjugate VLS-101 targeting ROR1 is effective in CAR T-resistant mantle cell lymphoma.

J Hematol Oncol 2021 08 28;14(1):132. Epub 2021 Aug 28.

Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA.

Mantle cell lymphoma (MCL) is a rare, aggressive and incurable subtype of non-Hodgkin's B-cell lymphoma. The principal barrier is frequent clinical relapse to multiple lines of therapies, including new FDA-approved biologics and cell therapy. Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton's tyrosine kinase inhibitors. However, relapses have inevitably occurred and once relapsed these patients display a very poor clinical outcome. Currently, there is no optional therapy specifically designed for these patients. The development of tailored and more efficacious therapies is therefore critical and represents a new medical need. We found that while the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed across most of the MCL cells, it is significantly elevated in CAR T-relapsed MCL tumors. To see whether this aberrant ROR1 expression contributed to CAR T resistance, we targeted ROR1 using VLS-101, a monomethyl auristatin E conjugated anti-ROR1 antibody. VLS-101 showed potent anti-MCL activity in vitro in ROR1-expressing MCL cell lines and ex vivo in primary patient samples. Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax. These data advocate for targeting ROR1 as a viable approach in the treatment of ROR1-positive MCL tumors, especially those with failure to prior therapies. These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.
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http://dx.doi.org/10.1186/s13045-021-01143-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400406PMC
August 2021

American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma.

Transplant Cell Ther 2021 09;27(9):720-728

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1016/j.jtct.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447221PMC
September 2021

Hydrolysis of a second Asp-Pro site at the N-terminus of NOTCH3 in inherited vascular dementia.

Sci Rep 2021 08 26;11(1):17246. Epub 2021 Aug 26.

Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA.

Cerebrovascular pathology at the biochemical level has been informed by the study of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a vascular disorder caused by NOTCH3 mutations. Previous work in CADASIL described N-terminal proteolysis of NOTCH3 generated by specific non-enzymatic cleavage of the first Asp-Pro sequence of the protein. Here, we investigated whether the second Asp-Pro peptide bond (residues 121-122) of NOTCH3 is cleaved in CADASIL. Monospecific antibodies were generated that recognize the neo-epitope predicted to be generated by cleavage after Asp121. These antibodies were used to localize cleavage events at Asp121 in post-mortem CADASIL and control brain tissue and to investigate factors that regulate cleavage at Asp121. We report that cleavage at Asp121 occurs at a high level in the arterial media of CADASIL cerebral arteries. Leptomeningeal arteries demonstrated substantially more cleavage product than penetrating arteries in the white matter, and control vessels harbored only a small amount of cleaved NOTCH3. Proteolysis at Asp121 occurred in purified preparations of NOTCH3 ectodomain, was increased by acidic pH and reductive conditions, and required native protein conformation for cleavage. Increasing the concentration of NOTCH3 EGF-like domain protein elevated the level of proteolysis. On the other hand, several polyanionic chemicals potently blocked cleavage at Asp121. These studies demonstrate that the NOTCH3 protein in CADASIL is cleaved in multiple locations at labile Asp-Pro peptide bonds. As such, chronic brain vascular disease, like other neurodegenerative conditions, features proteolysis of pathological proteins at multiple sites which may generate small pathological peptides.
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http://dx.doi.org/10.1038/s41598-021-96679-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390697PMC
August 2021

Gestational Diabetes and Overweight/Obesity: Analysis of Nulliparous Women in the U.S., 2011-2019.

Am J Prev Med 2021 Aug 23. Epub 2021 Aug 23.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Introduction: The rates of gestational diabetes mellitus are increasing in parallel with the rates of overweight and obesity. This analysis examines nationwide trends in the population-attributable fraction for gestational diabetes mellitus associated with prepregnancy overweight and obesity.

Methods: A serial, cross-sectional study was performed using U.S. population-based birth data files maintained by the National Center for Health Statistics between 2011 and 2019. Live singleton births to nulliparous women aged 15-44 years were included, and all analyses were stratified by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, non-Hispanic Asian). Prevalences of prepregnancy overweight (25.0-29.9 kg/m and 23.0-27.4 kg/m) and obesity (≥30.0 kg/m and ≥27.5 kg/m) based on standard and Asian-specific BMI categories, respectively, were quantified. Logistic regression estimated the adjusted associations between prepregnancy overweight and obesity and gestational diabetes mellitus, with normal weight (18.0-24.9 kg/mand 18.0-22.9 kg/m) as the ref. Annual population-attributable fractions for gestational diabetes mellitus associated with prepregnancy overweight and obesity were calculated, which account for both the prevalence of the risk factor and the associated risk of gestational diabetes mellitus.

Results: Among 11,950,881 included women, the mean maternal age was 26.3 years. From 2011 to 2019, the population-attributable fractions for gestational diabetes mellitus associated with overweight were stable (Hispanic: 12.0%-11.3%, non-Hispanic Asian: 12.1%-11.6%, p≥0.20) or decreased (non-Hispanic White: 10.8%-9.4%, non-Hispanic Black: 12.3%-9.2%, p<0.002); the population-attributable fractions for gestational diabetes mellitus associated with obesity were stable (non-Hispanic Black: 36.3%-37.9%, p=0.11) or increased (non-Hispanic White: 30.9%-33.3%, Hispanic: 27.2%-33.3%, non-Hispanic Asian 12.2%-15.4%, p<0.001).

Conclusions: The population-attributable fractions for gestational diabetes mellitus associated with obesity largely increased in the past decade, underscoring the importance of optimizing weight before pregnancy.
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http://dx.doi.org/10.1016/j.amepre.2021.05.036DOI Listing
August 2021

Trends in Prepregnancy Obesity and Association With Adverse Pregnancy Outcomes in the United States, 2013 to 2018.

J Am Heart Assoc 2021 Sep 25;10(17):e020717. Epub 2021 Aug 25.

Department of Preventive Medicine Northwestern University Feinberg School of Medicine Chicago IL.

Background The prevalence of obesity in the population has increased in parallel with increasing rates of adverse pregnancy outcomes (APOs). Quantifying contemporary trends in prepregnancy obesity and associations with interrelated APOs (preterm birth, low birth weight, and pregnancy-associated hypertension) together and individually can inform prevention strategies to optimize cardiometabolic health in women and offspring. Methods and Results We performed a serial, cross-sectional study using National Center for Health Statistics birth certificate data including women aged 15 to 44 years with live singleton births between 2013 and 2018, stratified by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Asian). We quantified the annual prevalence of prepregnancy obesity (body mass index ≥30.0 kg/m; body mass index ≥27.5 kg/m if non-Hispanic Asian). We then estimated adjusted associations using multivariable logistic regression (odds ratios and population attributable fractions) for obesity-related APOs compared with normal body mass index (18.5-24.9 kg/m; 18.5-22.9 kg/m if non-Hispanic Asian). Among 20 139 891 women, the prevalence of prepregnancy obesity increased between 2013 and 2018: non-Hispanic White (21.6%-24.8%), non-Hispanic Black (32.5%-36.2%), Hispanic (26.0%-30.5%), and non-Hispanic Asian (15.3%-18.6%) women (-trend < 0.001 for all). Adjusted odds ratios (95% CI) for APOs associated with obesity increased between 2013 and 2018, and by 2018, ranged from 1.27 (1.25-1.29) in non-Hispanic Black to 1.94 (1.92-1.96) in non-Hispanic White women. Obesity was most strongly associated with pregnancy-associated hypertension and inconsistently associated with preterm birth and low birth weight. Population attributable fractions of obesity-related APOs increased over the study period: non-Hispanic White (10.6%-14.7%), non-Hispanic Black (3.7%-6.9%), Hispanic (7.0%-10.4%), and non-Hispanic Asian (7.4%-9.7%) women (-trend < 0.01 for all). Conclusions The prevalence of prepregnancy obesity and burden of obesity-related APOs have increased, driven primarily by pregnancy-associated hypertension, and vary across racial/ethnic subgroups.
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http://dx.doi.org/10.1161/JAHA.120.020717DOI Listing
September 2021

ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma.

Bone Marrow Transplant 2021 Aug 20. Epub 2021 Aug 20.

Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1038/s41409-021-01288-9DOI Listing
August 2021

Trends in Gestational Diabetes at First Live Birth by Race and Ethnicity in the US, 2011-2019.

JAMA 2021 08;326(7):660-669

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: Gestational diabetes is associated with adverse maternal and offspring outcomes.

Objective: To determine whether rates of gestational diabetes among individuals at first live birth changed from 2011 to 2019 and how these rates differ by race and ethnicity in the US.

Design, Setting, And Participants: Serial cross-sectional analysis using National Center for Health Statistics data for 12 610 235 individuals aged 15 to 44 years with singleton first live births from 2011 to 2019 in the US.

Exposures: Gestational diabetes data stratified by the following race and ethnicity groups: Hispanic/Latina (including Central and South American, Cuban, Mexican, and Puerto Rican); non-Hispanic Asian/Pacific Islander (including Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese); non-Hispanic Black; and non-Hispanic White.

Main Outcomes And Measures: The primary outcomes were age-standardized rates of gestational diabetes (per 1000 live births) and respective mean annual percent change and rate ratios (RRs) of gestational diabetes in non-Hispanic Asian/Pacific Islander (overall and in subgroups), non-Hispanic Black, and Hispanic/Latina (overall and in subgroups) individuals relative to non-Hispanic White individuals (referent group).

Results: Among the 12 610 235 included individuals (mean [SD] age, 26.3 [5.8] years), the overall age-standardized gestational diabetes rate significantly increased from 47.6 (95% CI, 47.1-48.0) to 63.5 (95% CI, 63.1-64.0) per 1000 live births from 2011 to 2019, a mean annual percent change of 3.7% (95% CI, 2.8%-4.6%) per year. Of the 12 610 235 participants, 21% were Hispanic/Latina (2019 gestational diabetes rate, 66.6 [95% CI, 65.6-67.7]; RR, 1.15 [95% CI, 1.13-1.18]), 8% were non-Hispanic Asian/Pacific Islander (2019 gestational diabetes rate, 102.7 [95% CI, 100.7-104.7]; RR, 1.78 [95% CI, 1.74-1.82]), 14% were non-Hispanic Black (2019 gestational diabetes rate, 55.7 [95% CI, 54.5-57.0]; RR, 0.97 [95% CI, 0.94-0.99]), and 56% were non-Hispanic White (2019 gestational diabetes rate, 57.7 [95% CI, 57.2-58.3]; referent group). Gestational diabetes rates were highest in Asian Indian participants (2019 gestational diabetes rate, 129.1 [95% CI, 100.7-104.7]; RR, 2.24 [95% CI, 2.15-2.33]). Among Hispanic/Latina participants, gestational diabetes rates were highest among Puerto Rican individuals (2019 gestational diabetes rate, 75.8 [95% CI, 71.8-79.9]; RR, 1.31 [95% CI, 1.24-1.39]). Gestational diabetes rates increased among all race and ethnicity subgroups and across all age groups.

Conclusions And Relevance: Among individuals with a singleton first live birth in the US from 2011 to 2019, rates of gestational diabetes increased across all racial and ethnic subgroups. Differences in absolute gestational diabetes rates were observed across race and ethnicity subgroups.
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http://dx.doi.org/10.1001/jama.2021.7217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371572PMC
August 2021

Trends in prepregnancy cardiovascular health in the United States, 2011-2019.

Am J Prev Cardiol 2021 Sep 31;7:100229. Epub 2021 Jul 31.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL USA.

Objective: To evaluate contemporary patterns in prepregnancy cardiovascular health (CVH) in the United States (US).

Methods: We conducted a serial, cross-sectional study of National Center for Health Statistics Natality Data representing all live births in the US from 2011 to 2019. We assigned 1 point for each of four ideal prepregnancy metrics (nonsmoking and ideal body mass index [18.5-24.9 kg/m] provided by maternal self-report, and absence of hypertension and diabetes ascertained by the healthcare professional at delivery) to construct a prepregnancy clinical CVH score ranging from 0 to 4. We described the distribution of prepregnancy CVH, overall and stratified by self-reported race/ethnicity, age, insurance status, and receipt of the Women, Infants, and Children program (WIC) for supplemental nutrition. We examined trends by calculating average annual percent changes (AAPCs) in optimal prepregnancy CVH (score of 4).

Results: Of 31,643,982 live births analyzed between 2011 and 2019, 53.6% were to non-Hispanic White, 14.5% non-Hispanic Black, 23.3% Hispanic, and 6.6% non-Hispanic Asian women. The mean age (SD) was 28.5 (5.8) years. The prevalence (per 100 live births) of optimal prepregnancy CVH score of 4 declined from 42.1 to 37.7 from 2011 to 2019, with an AAPC (95% CI) of -1.4% per year (-1.3,-1.5). While the relative decline was observed across all race/ethnicity, insurance, and WIC subgroups, significant disparities persisted by race, insurance status, and receipt of WIC. In 2019, non-Hispanic Black women (28.7 per 100 live births), those on Medicaid (30.4), and those receiving WIC (29.1) had the lowest prevalence of optimal CVH.

Conclusions: Overall, less than half of pregnant women had optimal prepregnancy CVH, and optimal prepregnancy CVH declined in each race/ethnicity, age, insurance, and WIC subgroup between 2011-2019 in the US. However, there were persistent disparities by race/ethnicity and socioeconomic status.
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http://dx.doi.org/10.1016/j.ajpc.2021.100229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353467PMC
September 2021

Does stapedotomy improve high frequency conductive hearing?

Laryngoscope Investig Otolaryngol 2021 Aug 11;6(4):824-831. Epub 2021 Jun 11.

Department of Otolaryngology-Head and Neck Surgery Massachusetts Eye and Ear Infirmary Boston Massachusetts USA.

Objectives: Stapedotomy is performed to address conductive hearing deficits. While hearing thresholds reliably improve at low frequencies (LF), conductive outcomes at high frequencies (HF) are less reliable and have not been well described. Herein, we evaluate post-operative HF air-bone gap (ABG) changes and measure HF air conduction (AC) thresholds changes as a function of frequency.

Methods: Retrospective review of patients who underwent primary stapedotomy with incus wire piston prosthesis between January 2016 and May 2020. Pre- and postoperative audiograms were evaluated. LF ABG was calculated as the mean ABG of thresholds at 250, 500, and 1000 Hz. HF ABG was calculated at 4 kHz.

Results: Forty-six cases met criteria. Mean age at surgery was 54.0 ± 11.7 years. The LF mean preoperative ABG was 36.9 ± 11.0 dB and postoperatively this significantly reduced to 9.35 ± 6.76 dB, ( < .001). The HF mean preoperative ABG was 31.1 ± 14.4 dB and postoperatively, this also significantly reduced to 14.5 ± 12.3 dB, ( < .001). The magnitude of LF ABG closure was over 1.5 times the magnitude of HF ABG closure ( < .001). The gain in AC decreased with increasing frequency ( < .001).

Conclusion: Hearing improvement following stapedotomy is greater at low than high frequencies. Postoperative air bone gaps persist at 4 kHz. Further biomechanical and histopathologic work is necessary to localize postoperative high frequency conductive hearing deficits and improve stapedotomy hearing outcomes.

Level Of Evidence: 4, retrospective study.
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http://dx.doi.org/10.1002/lio2.599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356860PMC
August 2021

Safety and effectiveness of a risk-stratified venous thromboembolism prophylaxis algorithm in young people with cystic fibrosis.

Thromb Res 2021 Oct 10;206:36-41. Epub 2021 Jul 10.

Department of Pediatrics, Section of Pediatric Pulmonary and Sleep Medicine, Children's Hospital Colorado and the University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Background: People with cystic fibrosis (CF) have an increased risk of thrombosis due to acquired thrombophilia secondary to chronic systemic inflammation and central venous catheter use for treatment of pulmonary infections. The objective of this study is to determine the safety and effectiveness of a risk-stratified, venous thromboembolism (VTE) prophylaxis intervention.

Methods: This single-center, IRB-approved, retrospective study assessed patients with CF admitted to our institution for treatment of a pulmonary exacerbation from 2017 to 2019. Data and outcomes were manually extracted from the electronic medical record and internal CF clinical database. Subject characteristics, calculated VTE risk, prophylaxis interventions prescribed, VTE incidence, and adverse events were captured.

Results: A total of 135 CF patients had 354 admissions for pulmonary exacerbations in the time frame of the study. The majority of admissions (88.7%) were classified as moderate or high risk for VTE using the algorithm. Overall, VTE prophylaxis intervention determined by the algorithm was initiated in 36.2% of admissions. During the study period, no VTE events occurred. Four minor bleeding adverse effects were reported in patients receiving VTE chemical prophylaxis with enoxaparin (4.2%).

Conclusions: This study provides the first reported outcomes following implementation of a risk-stratified VTE prophylaxis algorithm in hospitalized young people with CF. In this population at increased risk, use of risk-stratified prophylaxis was safe and effective in preventing VTE. Additional work to improve and maintain adherence to the algorithm and VTE prophylaxis interventions at our institution is planned and similar care should be considered at other pediatric CF care centers.
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http://dx.doi.org/10.1016/j.thromres.2021.07.007DOI Listing
October 2021

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

Res Pract Thromb Haemost 2021 Jul 3;5(5):e12571. Epub 2021 Aug 3.

Hemophilia and Thrombosis Center University of Colorado Anschutz Medical Campus Aurora CO USA.

Background: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products.

Objective: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project.

Patients/methods: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor).

Results: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency.

Conclusions: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.
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http://dx.doi.org/10.1002/rth2.12571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331949PMC
July 2021

EZH2 expression is associated with inferior overall survival in mantle cell lymphoma.

Mod Pathol 2021 Aug 10. Epub 2021 Aug 10.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.
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http://dx.doi.org/10.1038/s41379-021-00885-9DOI Listing
August 2021

Recurrence of Disseminated Mycobacterium avium intracellulare Presenting as Spondylodiscitis and Epidural Abscess in a Patient with Acquired Immune Deficiency Syndrome (AIDS).

Am J Case Rep 2021 Aug 9;22:e931595. Epub 2021 Aug 9.

Department of Medicine, Spectrum Health Lakeland, Saint Joseph, MI, USA.

BACKGROUND Mycobacterium avium intracellulare complex (MAI) is a member of the non-tuberculous mycobacteria family, which can cause both pulmonary and non-pulmonary disease. In patients with advanced HIV, it is known to cause disseminated disease. We present a case of a 65-year-old man who has sex with men (MSM) with AIDS, found to have spondylodiscitis and an epidural abscess, who had recently completed treatment for disseminated MAI. CASE REPORT The patient was a 65-year-old with AIDS secondary to HIV and a prior history of disseminated MAI, who presented with severe back pain. Upon presentation to the hospital, an MRI was performed, which was suggestive of spondylodiscitis and an epidural abscess. He was taken to surgery for a minimally invasive T12-L1 laminectomy and evacuation of the epidural abscess. Both traditional cultures and acid-fast bacillus (AFB) cultures were negative. Due to worsening pain, he was taken back to surgery for a repeat debridement and biopsy. Repeat cultures were positive for MAI. He was started on rifabutin, ethambutol, azithromycin, and moxifloxacin. Moxifloxacin was subsequently discontinued. He has had problems tolerating the treatment regimen, but is planned to complete an 18-24-month course. CONCLUSIONS For patients with AIDS who have a diagnosis of spondylodiscitis and an epidural abscess, an opportunistic infection such as MAI should be considered. A repeat biopsy should be considered if suspicion is still high, even despite initially negative cultures. Treatment regimens should be prolonged, despite difficulty with medication compliance.
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http://dx.doi.org/10.12659/AJCR.931595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363659PMC
August 2021

Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K β/δ in relapsed refractory B cell lymphoma.

Leuk Lymphoma 2021 Aug 9:1-11. Epub 2021 Aug 9.

Karus Therapeutics Ltd., Harwell, UK.

PI3-kinase p110δ is mainly expressed in lymphocytes and is an attractive therapeutic target in B cell lymphomas. Targeting p110β may further suppress tumor growth and overcome escape mechanisms. KA2237 is an oral, potent, dual p110β/p110δ inhibitor. In preclinical studies, KA2237 inhibited p110β- and p110δ-dependent AKT activation and suppressed proliferation of diverse hematological and epithelial tumors. Twenty-one patients received KA2237 in a first-in-human phase I study (NCT02679196; diffuse large B cell,  = 8; follicular,  = 5; mantle cell,  = 3; chronic lymphocytic leukemia/small lymphocytic lymphoma,  = 3; marginal zone,  = 1; Waldenstrom's,  = 1). Median age 69; median prior therapies 3. Eighty-six percent of patients experienced treatment-related adverse events (TRAEs). Forty-three percent of patients experienced grade ≥3 TRAEs, with rash ( = 3), pneumonia ( = 3), transaminitis ( = 2), and pneumonitis ( = 2) being most common. Thirty-three percent discontinued treatment due to adverse events. KA2237 induced objective responses in indolent and aggressive lymphoma (overall response rate 37%; complete response  = 4, partial response  = 3).
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http://dx.doi.org/10.1080/10428194.2021.1957874DOI Listing
August 2021

A Flexible -SiC-Based Neural Interface Utilizing Pyrolyzed-Photoresist Film (C) Active Sites.

Micromachines (Basel) 2021 Jul 13;12(7). Epub 2021 Jul 13.

Department of Electrical Engineering, University of South Florida, Tampa, FL 33620, USA.

Carbon containing materials, such as graphene, carbon-nanotubes (CNT), and graphene oxide, have gained prominence as possible electrodes in implantable neural interfaces due to their excellent conductive properties. While carbon is a promising electrochemical interface, many fabrication processes are difficult to perform, leading to issues with large scale device production and overall repeatability. Here we demonstrate that carbon electrodes and traces constructed from pyrolyzed-photoresist-film (PPF) when combined with amorphous silicon carbide (SiC) insulation could be fabricated with repeatable processes which use tools easily available in most semiconductor facilities. Directly forming PPF on -SiC simplified the fabrication process which eliminates noble metal evaporation/sputtering and lift-off processes on small features. PPF electrodes in oxygenated phosphate buffered solution at pH 7.4 demonstrated excellent electrochemical charge storage capacity (CSC) of 14.16 C/cm, an impedance of 24.8 ± 0.4 kΩ, and phase angle of -35.9 ± 0.6° at 1 kHz with a 1.9 kµm recording site area.
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http://dx.doi.org/10.3390/mi12070821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304835PMC
July 2021
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