Publications by authors named "Michael Yang"

196 Publications

C1-2 cyst presenting with syringobulbia: a case report.

J Surg Case Rep 2021 Apr 6;2021(4):rjab097. Epub 2021 Apr 6.

Department of Neurosurgery, Tufts Medical Center, Boston, MA 02111, USA.

Extradural atlantoaxial cysts are typically related to C1-2 degeneration. Intradural cysts may cause secondary syringobulbia depending on the size and cerebrospinal fluid flow obstruction. However, medullary syrinxes have not been previously described with extradural cysts. Treatment of symptomatic lesions involves surgical resection, often via a far-lateral approach, with consideration of fusion if C1-2 instability is present. We present a case of an extradural C1-2 cyst with intradural extension causing syringobulbia. Effective surgical resection was accomplished via a far-lateral, partial transcondylar approach without fusion. It is important to recognize that cysts of extradural origin may exhibit intradural extension and compress critical neurovascular structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jscr/rjab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024048PMC
April 2021

Pericardiocentesis induced right ventricular changes in patients with and without pulmonary hypertension.

Echocardiography 2021 Apr 9. Epub 2021 Apr 9.

MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA.

Background: Pericardial effusion drainage in patients with significant pulmonary hypertension (PH) has been questioned because of hemodynamic collapse concern, mainly because of right ventricular (RV) function challenging assessment. We aimed to assess RV function changes related to pericardiocentesis in patients with and without PH.

Methods: Consecutive patients with symptomatic moderate-to-large pericardial effusion who had either echocardiographic or clinical signs of cardiac tamponade and who underwent pericardiocentesis from 2013 to 2018 were included. RV speckle-tracking echocardiography analysis was performed before and after pericardiocentesis. Patients were stratified by significant PH (pulmonary artery systolic pressure [PASP] ≥50 mm Hg).

Results: The study cohort consisted of 76 patients, 23 (30%) with PH. In patients with PH, both end-diastolic and end-systolic areas (EDA, ESA) increased significantly after pericardiocentesis (22.6 ± 8.0 cm -26.4 ± 8.4 cm , P = .01) and (15.9 ± 6.3 cm -18.7 ± 6.5 cm , P = .02), respectively. However, RV function indices including fractional area change (FAC: 30.6 ± 13.7%-29.1 ± 8.8%, P = .61) and free-wall longitudinal strain (FWLS: -16.7 ± 6.7 to -15.9 ± 5.0, P = .50) remained unchanged postpericardiocentesis. In contrast, in the non-PH group, after pericardiocentesis, EDA increased significantly (20.4 ± 6.2-22.4 ± 5.9 cm , P = .006) but ESA did not (14.9 ± 5.7 vs 15.0 ± 4.6 cm , P = .89), and RV function indices improved (FAC 27.9 ± 11.7%-33.1 ± 8.5%, P = .003; FWLS -13.6 ± 5.4 to -17.2 ± 3.9%, P < .001).

Conclusion: Quantification of RV size and function can improve understanding of echocardiographic and hemodynamic changes postpericardiocentesis, which has the potential to guide management of PH patients with large pericardial effusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/echo.15046DOI Listing
April 2021

Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

J Perinatol 2021 Mar 23. Epub 2021 Mar 23.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Objective: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial.

Study Design: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed.

Results: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40).

Conclusions: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-021-01018-5DOI Listing
March 2021

Pediatric Autoimmune Ocular Myasthenia Gravis: Evaluation of Presentation and Treatment Outcomes in a Large Cohort.

Pediatr Neurol 2021 Feb 5;118:12-19. Epub 2021 Feb 5.

Division of Pediatric Ophthalmology, Abrahamson Pediatric Eye Institute, Cincinnati, Ohio; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Background: In autoimmune myasthenia gravis (MG), autoantibodies target the neuromuscular junction. Ocular myasthenia gravis (OMG) is localized, affecting only extraocular and/or levator palpebrae muscles. OMG presents across all ages, varying in presentation, treatment modalities, and outcomes. Recently, there have been advances in MG/OMG treatment; their utilization and effectiveness are an important part of optimal disease management.

Methods: We completed a retrospective chart review of children aged 18 years or younger with a confirmed diagnosis of OMG presenting from 2002 to 2019.

Results: Forty-two patients were included with mean age at presentation of 8.5 years (2 to 18 years). Twenty-one patients (50%) had positive antibodies; 90% had acetylcholine receptor antibodies. Ten patients developed generalized symptoms with mean time to generalization of 13.6 months. Multiple logistic regression showed that older age of onset was a trend predictive factor (P = 0.054; odds ratio 1.17) for generalized disease. All patients were treated with pyridostigmine. Immunomodulating agents included steroids (15), mycophenolate mofetil (four), and intravenous immunoglobulin (one). Three patients underwent thymectomy. Twenty patients reached minimal manifestation status, and 12 achieved remission. Gender, race, and positive antibody status were not statistically significant predictors for advanced immunosuppressive therapy.

Conclusions: We summarize one of the largest cohorts of pediatric patients with OMG who have undergone up-to-date diagnostic and therapeutic regimens. The predictors of outcome and treatment pathway for OMG patients suggested by this report may be further elucidated by future prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2021.01.009DOI Listing
February 2021

Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313.

J Med Chem 2021 Mar 16;64(5):2714-2724. Epub 2021 Feb 16.

Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound (BMS-986251) led to tricyclic-carbocyclic analogues represented by - and culminated in the identification of (BMS-986313), with structural differences distinct from . The X-ray co-crystal structure of with the ligand binding domain of RORγt revealed several key interactions, which are different from . The in vitro and in vivo PK profiles of are described. In addition, we demonstrate robust efficacy of in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with in these models is comparable to the results observed with .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01992DOI Listing
March 2021

Creation of a dedicated line team for critically ill patients with COVID-19: A multidisciplinary approach to maximize resource utilization during the COVID-19 pandemic.

J Vasc Access 2021 Feb 4:1129729821991754. Epub 2021 Feb 4.

Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Pandemics create challenges for medical centers, which call for innovative adaptations to care for patients during the unusually high census, to distribute stress and work hours among providers, to reduce the likelihood of transmission to health care workers, and to maximize resource utilization.

Methods: We describe a multidisciplinary vascular access team's development to improve frontline providers' workflow by placing central venous and arterial catheters. Herein we describe the development, organization, and processes resulting in the rapid formation and deployment of this team, reporting on notable clinical issues encountered, which might serve as a basis for future quality improvement and investigation. We describe a retrospective, single-center descriptive study in a large, quaternary academic medical center in a major city. The COVID-19 vascular access team included physicians with specialized experience in placing invasive catheters and whose usual clinical schedule had been lessened through deferment of elective cases. The target population included patients with confirmed or suspected COVID-19 in the medical ICU (MICU) needing invasive catheter placement. The line team placed all invasive catheters on patients in the MICU with suspected or confirmed COVID-19.

Results And Conclusions: Primary data collected were the number and type of catheters placed, time of team member exposure to potentially infected patients, and any complications over the first three weeks. Secondary outcomes pertained to workflow enhancement and quality improvement. 145 invasive catheters were placed on 67 patients. Of these 67 patients, 90% received arterial catheters, 64% central venous catheters, and 25% hemodialysis catheters. None of the central venous catheterizations or hemodialysis catheters were associated with early complications. Arterial line malfunction due to thrombosis was the most frequent complication. Division of labor through specialized expert procedural teams is feasible during a pandemic and offloads frontline providers while potentially conferring safety benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1129729821991754DOI Listing
February 2021

Capnocytophaga canimorsus blebitis: case report and review of literature.

BMC Ophthalmol 2021 Jan 26;21(1):59. Epub 2021 Jan 26.

Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA, 92697, USA.

Background: Capnocytophaga canimorsus is a facultative anaerobic, slow-growing, capnophilic, Gram-negative bacillus, that is commonly found in the microflora of canine and feline oral cavities. Capnocytophaga infections are an emerging zoonotic disease that can cause fatal systemic infections in immunocompromised individuals. Localized ocular Capnocytophaga infections, including keratitis, blepharitis, and endophthalmitis, can lead to severe eye threatening situations. To our knowledge, there is currently no documented case of Capnocytophaga canimorsus blebitis with bleb perforation after trabeculectomy.

Case Presentation: Our case report and literature review features a novel case of Capnocytophaga blebitis that occurred after trabeculectomy, associated with close dog contact (i.e. face licking). The patient had underwent trabeculectomy 10 years prior and presented with conjunctival injection, perforated bleb, and hypotony. Overall, patient was medically treated subconjunctival vancomycin, gentamicin and moxifloxacin drops. Trabeculectomy revision was performed with good visual outcome. Bacterial cultures grew Capnocytophaga canimorsus.

Conclusions: We discuss the strategies for diagnosis, treatment, and common risk factors for ocular Capnocytophaga infections. At-risk patients with ocular infections should be asked about close contact with dogs and cats; and treated promptly with the proper antibiotic regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12886-021-01823-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839216PMC
January 2021

Bicyclic Ligand-Biased Agonists of S1P: Exploring Side Chain Modifications to Modulate the PK, PD, and Safety Profiles.

J Med Chem 2021 02 25;64(3):1454-1480. Epub 2021 Jan 25.

Bristol Myers Squibb Research & Early Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P modulator BMS-986104 () exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P; however, it demonstrated a long pharmacokinetic half-life ( 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of and , each of which are highly potent, biased agonists of S1P. These compounds not only exhibited shorter in vivo in multiple species but are also projected to have significantly shorter values in humans when compared to our first clinical candidate. In models of arthritis, treatment with and demonstrated robust efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01109DOI Listing
February 2021

Prediction tools for postoperative pain.

Pain Rep 2021 Jan-Feb;6(1):e875. Epub 2021 Jan 13.

Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PR9.0000000000000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810507PMC
January 2021

Consensus statement for perioperative care in lumbar spinal fusion: Enhanced Recovery After Surgery (ERAS®) Society recommendations.

Spine J 2021 Jan 12. Epub 2021 Jan 12.

Department of Anesthesiology, Pain Medicine and Procedural Sedation and Analgesia, Martini General Hospital Groningen, the Netherlands.

Background: Enhanced Recovery After Surgery (ERAS) evidence-based protocols for perioperative care have led to improvements in outcomes in numerous surgical areas, through multimodal optimization of patient pathway, reduction of complications, improved patient experience and reduction in the length of stay. ERAS represent a relatively new paradigm in spine surgery.

Purpose: This multidisciplinary consensus review summarizes the literature and proposes recommendations for the perioperative care of patients undergoing lumbar fusion surgery with an ERAS program.

Study Design: This is a review article.

Methods: Under the impetus of the ERAS® society, a multidisciplinary guideline development group was constituted by bringing together international experts involved in the practice of ERAS and spine surgery. This group identified 22 ERAS items for lumbar fusion. A systematic search in the English language was performed in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Systematic reviews, randomized controlled trials, and cohort studies were included, and the evidence was graded according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Consensus recommendation was reached by the group after a critical appraisal of the literature.

Results: Two hundred fifty-six articles were included to develop the consensus statements for 22 ERAS items; one ERAS item (prehabilitation) was excluded from the final summary due to very poor quality and conflicting evidence in lumbar spinal fusion. From these remaining 21 ERAS items, 28 recommendations were included. All recommendations on ERAS protocol items are based on the best available evidence. These included nine preoperative, eleven intraoperative, and six postoperative recommendations. They span topics from preoperative patient education and nutritional evaluation, intraoperative anesthetic and surgical techniques, and postoperative multimodal analgesic strategies. The level of evidence for the use of each recommendation is presented.

Conclusion: Based on the best evidence available for each ERAS item within the multidisciplinary perioperative care pathways, the ERAS® Society presents this comprehensive consensus review for perioperative care in lumbar fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.spinee.2021.01.001DOI Listing
January 2021

Commentary: Impact of Frailty on Outcomes Following Spine Surgery: A Prospective Cohort Analysis of 668 Patients.

Neurosurgery 2021 02;88(3):E236-E237

Department of Clinical Neurosciences, Division of Neurosurgery, University of Calgary, Calgary, Alberta, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyaa510DOI Listing
February 2021

Improving Speed of Cerebrospinal Fluid Collection Safely During Lumbar Punctures.

Ann Emerg Med 2021 01;77(1):129-130

Procedure Center, Department of Medicine, Department of Emergency Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annemergmed.2020.07.001DOI Listing
January 2021

Surge of Miller Fisher variant and Guillain-Barré syndrome in two downtown Los Angeles community teaching hospitals.

Clin Case Rep 2020 Nov 16;8(11):2245-2250. Epub 2020 Jul 16.

Department of Neurology Adventist Health White Memorial Los Angeles CA USA.

Guillain-Barré syndrome (GBS) and Miller Fisher variant (MFv) cases spiked threefold in Los Angeles, with a high proportion of MFv cases. MFv is underdiagnosed when accompanying neurological symptoms are mild. This report emphasizes the seasonality of GBS and its relation to ganglioside antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.3132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669403PMC
November 2020

A prognostic model for overall survival of patients with early-stage non-small cell lung cancer: a multicentre, retrospective study.

Lancet Digit Health 2020 11 19;2(11):e594-e606. Epub 2020 Oct 19.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA.

Background: Intratumoural heterogeneity has been previously shown to be related to clonal evolution and genetic instability and associated with tumour progression. Phenotypically, it is reflected in the diversity of appearance and morphology within cell populations. Computer-extracted features relating to tumour cellular diversity on routine tissue images might correlate with outcome. This study investigated the prognostic ability of computer-extracted features of tumour cellular diversity (CellDiv) from haematoxylin and eosin (H&E)-stained histology images of non-small cell lung carcinomas (NSCLCs).

Methods: In this multicentre, retrospective study, we included 1057 patients with early-stage NSCLC with corresponding diagnostic histology slides and overall survival information from four different centres. CellDiv features quantifying local cellular morphological diversity from H&E-stained histology images were extracted from the tumour epithelium region. A Cox proportional hazards model based on CellDiv was used to construct risk scores for lung adenocarcinoma (LUAD; 270 patients) and lung squamous cell carcinoma (LUSC; 216 patients) separately using data from two of the cohorts, and was validated in the two remaining independent cohorts (comprising 236 patients with LUAD and 335 patients with LUSC). We used multivariable Cox regression analysis to examine the predictive ability of CellDiv features for 5-year overall survival, controlling for the effects of clinical and pathological parameters. We did a gene set enrichment and Gene Ontology analysis on 405 patients to identify associations with differentially expressed biological pathways implicated in lung cancer pathogenesis.

Findings: For prognosis of patients with early-stage LUSC, the CellDiv LUSC model included 11 discriminative CellDiv features, whereas for patients with early-stage LUAD, the model included 23 features. In the independent validation cohorts, patients predicted to be at a higher risk by the univariable CellDiv model had significantly worse 5-year overall survival (hazard ratio 1·48 [95% CI 1·06-2·08]; p=0·022 for The Cancer Genome Atlas [TCGA] LUSC group, 2·24 [1·04-4·80]; p=0·039 for the University of Bern LUSC group, and 1·62 [1·15-2·30]; p=0·0058 for the TCGA LUAD group). The identified CellDiv features were also found to be strongly associated with apoptotic signalling and cell differentiation pathways.

Interpretation: CellDiv features were strongly prognostic of 5-year overall survival in patients with early-stage NSCLC and also associated with apoptotic signalling and cell differentiation pathways. The CellDiv-based risk stratification model could potentially help to determine which patients with early-stage NSCLC might receive added benefit from adjuvant therapy.

Funding: National Institue of Health and US Department of Defense.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s2589-7500(20)30225-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646741PMC
November 2020

Application of dual energy CT in the diagnosis of amiodarone lung toxicity as a cause of lung mass.

Clin Imaging 2021 Feb 22;70:46-48. Epub 2020 Oct 22.

University Hospitals Cleveland Medical Center, Cleveland, OH, United States of America.

Background: Diagnosis of amiodarone lung toxicity on computerized tomography (CT) can be challenging especially in the presence of mass-like consolidation. Additional causes of mass-like consolidation including malignancy and pneumonia should be excluded, sometimes requiring tissue sampling.

Case: Here we present a case of amiodarone lung toxicity, with diagnosis suspected based on patient's history of chronic cardiac disease, amiodarone treatment, and imaging characteristics. Evaluation with dual energy CT demonstrated high iodine content in the mass-like consolidation further supporting the diagnosis. Biopsy of the mass-like consolidation confirmed amiodarone toxicity.

Conclusion: Dual energy CT has potential utility in differentiating mass-like consolidation from other etiologies such as malignancy or pneumonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinimag.2020.10.024DOI Listing
February 2021

Identification of RUNX1T1 as a potential epigenetic modifier in small-cell lung cancer.

Mol Oncol 2021 01 27;15(1):195-209. Epub 2020 Nov 27.

Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, USA.

Small-cell lung cancer (SCLC) can be subgrouped into common 'pure' and rare 'combined' SCLC (c-SCLC). c-SCLC features a mixed tumor histology of both SCLC and non-small-cell lung cancer (NSCLC). We performed targeted exome sequencing on 90 patients with SCLC, including two with c-SCLC, and discovered RUNX1T1 amplification specific to small cell tumors of both patients with c-SCLC, but in only 2 of 88 'pure' SCLC patients. RUNX1T1 was first identified in the fusion transcript AML1/ETO, which occurs in 12%-15% of acute myelogenous leukemia (AML). We further show higher expression of RUNX1T1 in the SCLC component of another c-SCLC tumor by in situ hybridization. RUNX1T1 expression was enriched in SCLC compared with all other cancers, including NSCLC, in both cell lines and tumor specimens, as shown by mRNA level and western blotting. Transcriptomic analysis of hallmark genes decreased by stable RUNX1T1 overexpression revealed a significant change in E2F targets. Validation experiments in multiple lung cancer cell lines showed that RUNX1T1 overexpression consistently decreased CDKN1A (p21) expression and increased E2F transcriptional activity, which is commonly altered in SCLC. Chromatin immunoprecipitation (ChIP) in these overexpressing cells demonstrated that RUNX1T1 interacts with the CDKN1A (p21) promoter region, which displayed parallel reductions in histone 3 acetylation. Furthermore, reduced p21 expression could be dramatically restored by HDAC inhibition using Trichostatin A. Reanalysis of ChIP-seq data in Kasumi-1 AML cells showed that knockdown of the RUNX1T1 fusion protein was associated with increased global acetylation, including the CDKN1A (p21) promoter. Thus, our study identifies RUNX1T1 as a biomarker and potential epigenetic regulator of SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782087PMC
January 2021

Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P) Modulators: Optimization of the PK, PD, and Safety Profiles.

ACS Med Chem Lett 2020 Sep 11;11(9):1766-1772. Epub 2020 Aug 11.

Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of and led to the identification of aryl ether and thioether-derived bicyclic S1P differentiated modulators -. The effects of analogs - on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded , and the predicted margin of safety against the cardiovascular effects of would be large enough for human studies. Importantly, compared to and , compound had a better profile in both potency (ED < 0.05 mg/kg) and predicted human half-life ( ∼ 5 days).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488280PMC
September 2020

Central Venous Catheter Insertion in the Prone Position-A Last Resort in Critically Ill COVID-19 Patients.

J Intensive Care Med 2021 Mar 16;36(3):373-375. Epub 2020 Sep 16.

Procedure Center, COVID-19 line team, Department of Medicine, 22494Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: In the setting of the COVID pandemic, many patients falling ill with acute respiratory distress syndrome eventually require prone positioning for gas exchange. Traditionally, central venous catheters are inserted with patient in the supine or Trendelenburg position. However, when a patient cannot tolerate supine position and the need for central venous access is urgent, catheter placement may be considered with the patient in the prone position.

Case Summary: A 69-year-old male with rapidly declining respiratory status secondary to COVID pneumonia quickly developed acute respiratory distress syndrome, was rapidly intubated, and then placed in the prone position. Patient could not tolerate the supine position even briefly and required a central venous catheter insertion for continuous renal replacement therapy. We kept the patient in the prone position and successfully inserted a central venous catheter in such position with real-time ultrasound guidance and using micropuncture technique.

Conclusion: In the setting of the COVID pandemic, many cases of acute respiratory distress syndrome require patients to be prone in order to improve gas exchange. In the most severe situations, these patients would not be able to tolerate rotating back to the supine position but would still require central venous catheter insertion urgently. We demonstrated feasibility of central venous catheter insertion in the prone position in these severely ill patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0885066620959649DOI Listing
March 2021

Development and validation of a clinical prediction score for poor postoperative pain control following elective spine surgery.

J Neurosurg Spine 2020 Sep 15:1-10. Epub 2020 Sep 15.

Departments of1Clinical Neurosciences, Section of Neurosurgery.

Objective: Thirty percent to sixty-four percent of patients experience poorly controlled pain following spine surgery, leading to patient dissatisfaction and poor outcomes. Identification of at-risk patients before surgery could facilitate patient education and personalized clinical care pathways to improve postoperative pain management. Accordingly, the aim of this study was to develop and internally validate a prediction score for poorly controlled postoperative pain in patients undergoing elective spine surgery.

Methods: A retrospective cohort study was performed in adult patients (≥ 18 years old) consecutively enrolled in the Canadian Spine Outcomes and Research Network registry. All patients underwent elective cervical or thoracolumbar spine surgery and were admitted to the hospital. Poorly controlled postoperative pain was defined as a mean numeric rating scale score for pain at rest of > 4 during the first 24 hours after surgery. Univariable analysis followed by multivariable logistic regression on 25 candidate variables, selected through a systematic review and expert consensus, was used to develop a prediction model using a random 70% sample of the data. The model was transformed into an eight-tier risk-based score that was further simplified into the three-tier Calgary Postoperative Pain After Spine Surgery (CAPPS) score to maximize clinical utility. The CAPPS score was validated using the remaining 30% of the data.

Results: Overall, 57% of 1300 spine surgery patients experienced poorly controlled pain during the first 24 hours after surgery. Seven significant variables associated with poor pain control were incorporated into a prediction model: younger age, female sex, preoperative daily use of opioid medication, higher preoperative neck or back pain intensity, higher Patient Health Questionnaire-9 depression score, surgery involving ≥ 3 motion segments, and fusion surgery. Notably, minimally invasive surgery, body mass index, and revision surgery were not associated with poorly controlled pain. The model was discriminative (C-statistic 0.74, 95% CI 0.71-0.77) and calibrated (Hosmer-Lemeshow goodness-of-fit, p = 0.99) at predicting the outcome. Low-, high-, and extreme-risk groups stratified using the CAPPS score had 32%, 63%, and 85% predicted probability of experiencing poorly controlled pain, respectively, which was mirrored closely by the observed incidence of 37%, 62%, and 81% in the validation cohort.

Conclusions: Inadequate pain control is common after spine surgery. The internally validated CAPPS score based on 7 easily acquired variables accurately predicted the probability of experiencing poorly controlled pain after spine surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2020.5.SPINE20347DOI Listing
September 2020

Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.

Bioorg Med Chem Lett 2020 12 31;30(23):127521. Epub 2020 Aug 31.

Research and Early Development, Bristol Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08543, United States.

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127521DOI Listing
December 2020

Natural history of inflammatory and non-inflammatory dry eye in thyroid eye disease.

Orbit 2020 Aug 26:1-5. Epub 2020 Aug 26.

Stein Eye Institute, University of California , Los Angeles, USA.

Purpose: The purpose is to understand the natural history and physical findings in thyroid eye disease (TED) patients with severe dry eye symptoms (DES).

Methods: Prospective cohort study, studying DES in TED patients over two years. Baseline data included clinical activity score (CAS), time since disease onset, punctate epithelial erosions (PEE), lagophthalmos, superior limbic keratoconjunctivitis (SLK), and marginal reflex distance 1 (MRD1). Ocular Surface Disease Index (OSDI) was utilized to measure symptomatology and scores > 33 (severe) were the primary outcome measure. Multivariate logistic regression was performed on two groups (<9 months, >9 months) to assess if variables change in early versus late disease.

Results: 88 met the inclusion criteria. 80.7% (n = 71) were female. There were 42 patients in the group with onset of symptoms under nine months and 46 patients over nine months. Mean CAS score was greater under nine months (2.45) than over nine months (1.29) ( < .05). In the multivariate logistic regression for the group presenting with symptoms under nine months, CAS was the only significant predictor of severe OSDI. Every increase in CAS of one yielded a 2.0x increased risk of severe OSDI. For the patients over nine months from onset, PEE was the significant predictor of severe OSDI. PEE was associated with a 5.9x increased risk of severe OSDI.

Conclusions: Severe DES correlate with inflammatory features within the first nine months. Afterward, presence of PEE became more important. DES in TED tends to be a manifestation of orbital inflammation early in disease and exposure later.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01676830.2020.1814352DOI Listing
August 2020

Left Parietal Tumors Presenting with Smartphone Icon Visual Agnosia: Two Cases of a Modern Presentation of Gerstmann Syndrome.

World Neurosurg 2020 10 13;142:233-238. Epub 2020 Jul 13.

Department of Neurosurgery, Tufts Medical Center, Boston, Massachusetts, USA. Electronic address:

Background: Gerstmanns syndrome-a clinical constellation of left-right confusion, finger agnosia, agraphia, and acalculia-is frequently attributed to pathology in the dominant inferior parietal lobe or temporo-occipital region. However, these unique clinical findings are often accompanied by more subtle signs, including aphasias, neglect, and agnosias. Associative visual agnosia, in which a patient is able to accurately perceive and describe but not recognize an object or symbol, is a well-documented but infrequently observed clinical entity.

Case Description: Here we detail 2 unique cases of patients who presented with the inability to recognize and use smartphone application icons. Both were found to have left temporo-occipital tumors displacing the left temporo-parietooccipital cortex.

Conclusions: In the era of pervasive technology, we emphasize that smartphone icon associative visual agnosias may be recognized by discerning physicians in the clinical diagnosis of dominant parietal lobe pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.07.030DOI Listing
October 2020

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility.

Mil Med 2020 09;185(9-10):e1420-e1427

Department of Behavioral Health, Tripler Army Medical Center, 1 Jarrett White Rd., TAMC, HI, 96859.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression has been studied for over two decades. Repetitive TMS was approved by the Food and Drug Administration in 2008 for the treatment of depression after at least one failed trial of an antidepressant medication of adequate dose and duration. This study evaluated whether rTMS treatments may be associated with measurable improvements in depression and post-traumatic stress disorder (PTSD) symptoms for treated military beneficiaries in Hawaii suffering from depression. It also examined the number of failed medication trials that patients underwent before rTMS treatment.

Materials And Methods: A retrospective chart review of 77 rTMS patients who received and completed treatment between January 1, 2010 and October 31, 2016 was performed. Under a typical treatment regimen, patients receive rTMS for 6 weeks as well as weekly psychiatric assessments, which included completion of Beck's Depression Inventory (BDI) and PTSD Checklist (PCL). A mixed model repeated measures analysis was done assuming an autoregressive order one covariance structure to evaluate changes over time. Adjusted analyses were done to assess whether changes over time differed by age, prior diagnosis of PTSD, active duty status, and gender.

Results: The majority of patients were from the army (74%) and 56% were on active duty. Just over half (53%) were male. Most patients (52%) had completed trials of three or more different antidepressant medications before initiation of treatment with rTMS. The mean number of antidepressant trials was 2.7. BDI and PCL scores were significantly lower at end of treatment on average compared to the pretreatment baseline scores. Mean differences for BDI and PCL were significant with P < 0.001 15, 30, and 45 days after TMS treatment was initiated. Overall, 44% of patients experienced a reduction ≥10 points on BDI, and 38% experienced a reduction ≥10 points on PCL. Additionally, scores fell similarly regardless of whether or not patients had a comorbid diagnosis of PTSD.

Conclusions: Our research suggests that rTMS treatments may produce a reduction in symptoms of both depression and PTSD in patients with refractory depression and comorbid PTSD. It may be a useful alternative to antidepressants in the treatment of depression in the military population, including those with comorbid PTSD. Broader implementation of this treatment modality may prove beneficial for the purposes of military readiness, given current policies and restrictions on service members who are initiated on antidepressant medications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/milmed/usaa148DOI Listing
September 2020

TNFR2 blockade alone or in combination with PD-1 blockade shows therapeutic efficacy in murine cancer models.

J Leukoc Biol 2020 06 24;107(6):981-991. Epub 2020 May 24.

Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Immune checkpoint inhibitors are profoundly transforming cancer therapy, but response rates vary widely. The efficacy of checkpoint inhibitors, such as anti-programmed death receptor-1 (anti-PD-1), might be increased by combination therapies. TNFR2 has emerged as a new target due to its massive expression on highly immunosuppressive regulatory T cells (Tregs) in the microenvironment and on certain tumor cells. In murine colon cancer models CT26 and MC38, we evaluated the efficacy of a new anti-TNFR2 antibody alone or in combination with anti-PD-1 therapy. Tumor-bearing mice were treated with placebo, anti-PD-1 alone, anti-TNFR2 alone, or combination anti-PD-1 and anti-TNFR2. We found that combination therapy had the greatest efficacy by complete tumor regression and elimination (cure) in 65-70% of animals. The next most effective therapy was anti-TNFR2 alone (20-50% cured), whereas the least effective was anti-PD-1 alone (10-25% cured). The mode of action, according to in vivo and in vitro methods including FACS analysis, was by killing immunosuppressive Tregs in the tumor microenvironment and increasing the ratio of CD8+ T effectors (Teffs) to Tregs. We also found that sequence of antibody delivery altered outcome. The two most effective sequences were simultaneous delivery (70% cured) followed by anti-TNFR2 preceding anti-PD-1 (40% cured), and the least effective was by anti-PD-1 preceding anti-TNFR2 (10% cured). We conclude that anti-PD-1 is best enhanced by simultaneous administration with anti-TNFR2, and anti-TNFR2 alone may be potentially useful strategy for those do not respond to, or cannot tolerate, anti-PD-1 or other checkpoint inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.5MA0420-375RRRRRDOI Listing
June 2020

Drug-induced Acute Angle-closure Glaucoma: A Review.

J Curr Glaucoma Pract 2019 Sep-Dec;13(3):104-109

Department of Ophthalmology, UCI Health Gavin Herbert Eye Institute, University of California, Irvine, California, USA.

Aim: Our goal is to review current literature regarding drug-induced acute angle-closure glaucoma (AACG) and provide ophthalmologists and general practitioners with a thorough understanding of inciting medications and treatment pitfalls to be avoided.

Background: Drug-induced AACG is an ophthalmological emergency that ophthalmologists and general practitioners should be familiar with, given its potentially blinding consequences. Common anatomical risk factors for AACG include a shallow anterior chamber depth, short axial length, plateau iris configuration, thick lens, anteriorly positioned lens, and rarely, intraocular tumor. Demographic risk factors include female sex, Asian ethnicity, family history, and advanced age. In patients with predisposing factors, acute angle closure can be triggered by various classes of medications including adrenergic agonists, anticholinergics, cholinergics, sulfonamides, supplements, and serotonergic medications. Physicians prescribing such inciting medications should be aware of their potentially sight-threatening adverse effects and to inform patients of the warning symptoms. Patients typically present with elevated intraocular pressure (IOP), headache, nausea, blurry vision, and halos around lights.

Review Results: There are two main mechanisms of drug-induced AACG, both with different treatment strategies. The first mechanism of drug-induced AACG is pupillary block and iridocorneal angle closure secondary to thickening of iris base with mydriasis. The second mechanism of drug-induced AACG is anterior displacement of the lens-iris diaphragm due to mass effect (e.g., blood, misdirected aqueous humor, and tumors), uveal effusion, or weakened zonules.

Conclusion: This paper reviews drug-induced AACG, high-risk anatomical features, underlying mechanisms, inciting medications, and options for treatment and prevention.

Clinical Significance: With proper understanding of the underlying mechanism of drug-induced AACG, physicians can respond promptly to save their patients' vision by employing the correct treatment strategy.

How To Cite This Article: Yang MC, Lin KY. Drug-induced Acute Angle-closure Glaucoma: A Review. J Curr Glaucoma Pract 2019;13(3):104-109.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5005/jp-journals-10078-1261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221246PMC
May 2020

Development and validation of next generation sequencing based 35-gene hereditary cancer panel.

Hered Cancer Clin Pract 2020 28;18. Epub 2020 Apr 28.

1Prenetics Limited, 7/F, Prosperity Millennia Plaza, 663 King's Road, Quarry Bay, Hong Kong SAR, China.

Background: Understanding the genetic basis of cancer risk is a major international endeavor. The emergence of next-generation sequencing (NGS) in late 2000's has further accelerated the discovery of many cancer susceptibility genes. The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has proven to be a viable option, with the accurate and robust detection of a wide range of clinically relevant variants in the targeted genes being crucial.

Methods: We have developed and validated a targeted NGS-based test for hereditary cancer risk assessment using Illumina's NGS platform by analyzing the protein-coding regions of 35 hereditary cancer genes with a bioinformatics pipeline that utilizes standard practices in the field. This 35-gene hereditary cancer panel is designed to identify germline cancer-causing mutations for 8 different cancers: breast, ovarian, prostate, uterine, colorectal, pancreatic, stomach cancers and melanoma. The panel was validated using well-characterized DNA specimens [NIGMS Human Genetic Cell Repository], where DNA had been extracted using blood of individuals whose genetic variants had been previously characterized by the 1000 Genome Project and the Coriell Catalog.

Results: The 35-gene hereditary cancer panel shows high sensitivity (99.9%) and specificity (100%) across 4820 variants including single nucleotide variants (SNVs) and small insertions and deletions (indel; up to 25 bp). The reproducibility and repeatability are 99.8 and 100%, respectively.

Conclusions: The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has been considered a viable option. In the present study, we developed and validated a 35-gene panel for testing 8 common cancers using next-generation sequencing (NGS). The performance of our hereditary cancer panel is assessed across a board range of variants in the 35 genes to support clinical use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13053-020-00141-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189534PMC
April 2020

Faster Recovery of Internal Ophthalmoplegia than External Ophthalmoplegia in a Miller Fisher Variant of Guillain-Barre Syndrome.

Case Rep Ophthalmol Med 2020 12;2020:7258327. Epub 2020 Apr 12.

Department of Neurology, Adventist Health White Memorial, Los Angeles, California, USA.

We present a case of classic Miller Fisher Syndrome (MFS) variant of Guillain-Barre Syndrome (GBS) with detailed description in the difference between the internal and external ophthalmoplegia. They are different in their onset, duration, and recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/7258327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174959PMC
April 2020

Short-term Outcomes After Very Low-Dose Intravitreous Bevacizumab for Retinopathy of Prematurity.

JAMA Ophthalmol 2020 06;138(6):698-701

Mayo Clinic, Rochester, Minnesota.

Importance: Intravitreous bevacizumab (0.25 mg to 0.625 mg) is commonly used to treat type 1 retinopathy of prematurity (ROP), but there are concerns about systemic toxicity, particularly the risk of neurodevelopmental delay. A much lower dose may be effective for ROP while reducing systemic risk. Previously, after testing doses of 0.25 mg to 0.031 mg, doses as low as 0.031 mg were found to be effective in small cohorts of infants.

Objective: To find the lowest dose of intravitreous bevacizumab effective for severe ROP.

Design, Setting, And Participants: Between April 2017 and May 2019, 59 premature infants with type 1 ROP in 1 or both eyes were enrolled in a masked, multicenter, dose de-escalation study. In cohorts of 10 to 14 infants, 1 eye per infant received 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreous bevacizumab. Diluted bevacizumab was prepared by individual research pharmacies and delivered using 300-µL syringes with 5/16-inch, 30-guage fixed needles. Analysis began July 2019.

Interventions: Bevacizumab intravitreous injections at 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg.

Main Outcomes And Measures: Success was defined as improvement by 4 days postinjection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks.

Results: Fifty-five of 59 enrolled infants had 4-week outcomes completed; the mean (SD) birth weight was 664 (258) g, and the mean (SD) gestational age was 24.8 (1.6) weeks. A successful 4-week outcome was achieved for 13 of 13 eyes (100%) receiving 0.016 mg, 9 of 9 eyes (100%) receiving 0.008 mg, 9 of 10 eyes (90%) receiving 0.004 mg, but only 17 of 23 eyes (74%) receiving 0.002 mg.

Conclusions And Relevance: These data suggest that 0.004 mg may be the lowest dose of bevacizumab effective for ROP. Further investigation is warranted to confirm effectiveness of very low-dose intravitreous bevacizumab and its effect on plasma vascular endothelial growth factor levels and peripheral retinal vascularization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180729PMC
June 2020

Adverse Events After Transition From ICU to Hospital Ward: A Multicenter Cohort Study.

Crit Care Med 2020 Jul;48(7):946-953

Department of Critical Care Medicine, University of Calgary and Alberta Health Services, Calgary, AB, Canada.

Objectives: To examine adverse events and associated factors and outcomes during transition from ICU to hospital ward (after ICU discharge).

Design: Multicenter cohort study.

Setting: Ten adult medical-surgical Canadian ICUs.

Patients: Patients were those admitted to one of the 10 ICUs from July 2014 to January 2016.

Interventions: None.

Measurements And Main Results: Two ICU physicians independently reviewed progress and consultation notes documented in the medical record within 7 days of patient's ICU discharge date to identify and classify adverse events. The adverse event data were linked to patient characteristics and ICU and ward physician surveys collected during the larger prospective cohort study. Analyses were conducted using multivariable logistic regression. Of the 451 patients included in the study, 84 (19%) experienced an adverse event, the majority (62%) within 3 days of transfer from ICU to hospital ward. Most adverse events resulted only in symptoms (77%) and 36% were judged to be preventable. Patients with adverse events were more likely to be readmitted to the ICU (odds ratio, 5.5; 95% CI, 2.4-13.0), have a longer hospital stay (mean difference, 16.1 d; 95% CI, 8.4-23.7) or die in hospital (odds ratio, 4.6; 95% CI, 1.8-11.8) than those without an adverse event. ICU and ward physician predictions at the time of ICU discharge had low sensitivity and specificity for predicting adverse events, ICU readmissions, and hospital death.

Conclusions: Adverse events are common after ICU discharge to hospital ward and are associated with ICU readmission, increased hospital length of stay and death and are not predicted by ICU or ward physicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004327DOI Listing
July 2020

The use of decompressive segmental sublaminoplasty to treat myelopathy caused by lumbar stenosis in tethered cord syndrome.

J Surg Case Rep 2020 Mar 24;2020(3):rjaa041. Epub 2020 Mar 24.

Tufts University School of Medicine, Boston, MA, USA.

A 79-year-old woman presented with acute-onset right leg pain in the setting of 3 months of progressive gait deterioration and bilateral leg weakness. On exam she had right lower extremity hyperreflexia and weakness. Lumbar spine magnetic resonance imaging demonstrated L3-L5 central canal stenosis with L4-L5 spondylolisthesis and a previously undiagnosed tethered cord. She underwent minimally invasive left segmental sublaminoplasty at L3-L4 and L4-L5 for spinal cord decompression with onlay arthrodesis resulting in resolution of her radicular pain and improved strength. This is a unique case of lumbar spinal stenosis presenting with myelopathy in the context of a previously asymptomatic and undiagnosed tethered cord.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jscr/rjaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092679PMC
March 2020