Publications by authors named "Michael James"

528 Publications

Individualized Homeopathic Medicines in Stage I Essential Hypertension: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial.

J Altern Complement Med 2021 Mar 23. Epub 2021 Mar 23.

Department of Repertory, D. N. De Homoeopathic Medical College and Hospital, Government of West Bengal, Kolkata, India.

The present study assessed the feasibility of a definitive placebo-controlled trial for evaluating individualized homeopathy (IH) in stage I hypertension (HTN). Double-blind, randomized (IH: 34, placebo: 34), placebo-controlled, parallel arms, pilot trial. National Institute of Homoeopathy, India. Patients suffering from stage I HTN. IH and identical-looking placebo. Feasibility issues, blood pressure (BP) and Measure Yourself Medical Outcome Profile-2 (MYMOP-2) were assessed for 6 months. The recruitment and retention rates were 44.4% and 85.3%, respectively. Group differences were seemingly higher in the IH group than in the placebo group. Despite challenges in recruitment, an adequately powered efficacy trial appears feasible in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/acm.2020.0222DOI Listing
March 2021

Individualized Homeopathic Medicines in the Treatment of Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled, Pilot Trial.

Complement Med Res 2021 Mar 4:1-11. Epub 2021 Mar 4.

Independent Researcher, Howrah, India.

Introduction: Evidence favoring homeopathy in generalized anxiety disorder (GAD) remains scarce. The objective of this pilot trial was to test feasibility of a definitive trial in future. We also experimented whether individualized homeopathic medicines (IH) plus psychological counseling (PC) can produce significantly different effects beyond placebo plus PC in the treatment of GAD.

Methods: A double-blind, randomized, placebo-controlled, parallel arm, pilot trial was conducted on 62 GAD patients at the National Institute of Homoeopathy, India. GAD-7 questionnaire and Hamilton Anxiety Scale (HAM-A) were used as the primary and secondary outcomes, respectively, measured at baseline and 3 months. Patients received either IH plus PC (n = 31) or identical-looking placebo plus PC (n = 31). Intention-to-treat sample was analyzed to detect group differences using unpaired t tests.

Results: Recruitment and retention rates were 56 and 90%, respectively. Mean age was 31.5 years; 56.5% were male. GAD-7 reductions were non-significantly higher in IH than placebo (p = 0.122). Group differences on HAM-A favored IH significantly (p = 0.018). Effect sizes were small to medium. Calcarea carbonica was the most frequently indicated medicine. No serious adverse events happened.

Conclusions: A small but positive direction of anxiolytic effect was observed favoring homeopathy over placebo. A definitive trial appeared feasible in future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000514524DOI Listing
March 2021

Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance.

NPJ Precis Oncol 2021 Mar 2;5(1):16. Epub 2021 Mar 2.

Essential Biotechnology LLC, Big Bend, WI, United States.

Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients' serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-021-00152-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925570PMC
March 2021

A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines.

Org Lett 2021 Mar 1;23(6):2063-2068. Epub 2021 Mar 1.

Department of Chemistry, University of York, Heslington, York, U.K.., YO10 5DD.

An operationally simple, high yielding three-step cascade process is described for the direct conversion of indole-tethered ynones into functionalized quinolines. A single "multitasking" thiol reagent is used to promote a three-step dearomatizing spirocyclization, nucleophilic substitution, and one-atom ring expansion reaction cascade under remarkably mild conditions. In addition, a novel route to thio-oxindoles is described, which was discovered by serendipity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.1c00205DOI Listing
March 2021

Platelet FcγRIIA in immunity and thrombosis: Adaptive immunothrombosis.

J Thromb Haemost 2021 Feb 15. Epub 2021 Feb 15.

Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Sepsis and autoimmune diseases remain major causes of morbidity and mortality. The last decade has seen a new appreciation of platelets in host defense, in both immunity and thrombosis. Platelets are first responders in the blood to microbes or non-microbial antigens. The role of platelets in physiologic immunity is counterbalanced by their role in pathology, for example, microvascular thrombosis. Platelets encounter microbes and antigens via both innate and adaptive immune processes; platelets also help to shape the subsequent adaptive response. FcγRIIA is a receptor for immune complexes opsonized by IgG or pentraxins, and expressed in humans by platelets, granulocytes, monocytes and macrophages. With consideration of the roles of IgG and Fc receptors, the host response to microbes and autoantigens can be called adaptive immunothrombosis. Here we review newer developments involving platelet FcγRIIA in humans and humanized mice in immunity and thrombosis, with special attention to heparin-induced thrombocytopenia, systemic lupus erythematosus, and bacterial sepsis. Human genetic diversity in platelet receptors and the utility of humanized mouse models are highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15265DOI Listing
February 2021

A Triage Model for Interhospital Transfers of Low Risk Intracerebral Hemorrhage Patients.

J Stroke Cerebrovasc Dis 2021 Apr 18;30(4):105616. Epub 2021 Jan 18.

Division of Neurology, Prisma Health-Upstate, 200 Patewood Drive, Suite B350, Greenville, SC 29615, United States. Electronic address:

Objectives: Intracerebral hemorrhage comprises a large proportion of inter-hospital transfers to comprehensive stroke centers from centers without comprehensive stroke center resources despite lack of mortality benefit and low comprehensive stroke center resource utilization. The subset of patients who derive the most benefit from inter-hospital transfers is unclear. Here, we create a triage model to identify patients who can safely avoid transfer to a comprehensive stroke center.

Materials And Methods: A retrospective cohort of spontaneous intracerebral hemorrhage patients transferred to our comprehensive stroke center from surrounding centers was used. Patients with early discharge from the Neuroscience Intensive Care Unit without use of comprehensive stroke center resources were identified as low risk, non-utilizers. Variables associated with this designation were used to develop and validate a triage model.

Results: The development and replication cohorts comprised 358 and 99 patients respectively, of whom 78 (22%) and 26 (26%) were low risk, non-utilizers. Initial Glasgow Coma Scale and baseline hemorrhage volume were associated with low risk, non-utilizers in multivariate analysis. Initial Glasgow Coma Scale >13, intracerebral hemorrhage volume <15ml, absence of intraventricular hemorrhage, and supratentorial location had an area under curve, specificity, and sensitivity of 0.72, 91.4%, 52.6%, respectively, for identifying low risk, non-utilizers, and 0.75, 84.9%, 65.4%, respectively, in the replication cohort.

Conclusions: Spontaneous intracerebral hemorrhage patients with Glasgow Coma Scale >13, intracerebral hemorrhage volume <15 ml, absence of intraventricular hemorrhage, and supratentorial location might safely avoid inter-hospital transfer to a comprehensive stroke center. Validation in a prospective, multicenter cohort is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105616DOI Listing
April 2021

Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage.

Neurocrit Care 2021 Jan 21. Epub 2021 Jan 21.

Department of Neurology, Duke University, Durham, NC, USA.

Background: Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its isoform-specific neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age.

Methods: In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.

Results: In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91-153.70 and p < 0.001; 95% CI: 49.54-205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27-11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: - 0.037 to - 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η  = 0.093) and neuroseverity scores (p < 0.05; η = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: - 1.41 to - 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η = 0.111) but not neuroseverity scores (p > 0.05; η = 0.034).

Conclusions: Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12028-020-01184-yDOI Listing
January 2021

Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.

Neurocrit Care 2021 Jan 13. Epub 2021 Jan 13.

Duke University Medical Center, Department of Anesthesiology, DUMC 3094, Duke University, Durham, NC, 27710, USA.

Background/objective: Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.

Methods: We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay.

Results: There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64-2.52), need for tracheostomy (OR 2.10, 95% CI 1.52-2.89), PEG tube placement (OR 1.88, 95% CI 1.45-2.45), and increased hospital length of stay (p < 0.001).

Conclusions: The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12028-020-01183-zDOI Listing
January 2021

Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies.

J Med Chem 2021 01 7;64(2):1073-1102. Epub 2021 Jan 7.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.

Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01605DOI Listing
January 2021

Epidemiology and Outcomes of Acute Respiratory Distress Syndrome Following Isolated Severe Traumatic Brain Injury.

J Intensive Care Med 2020 Nov 15:885066620972001. Epub 2020 Nov 15.

Department of Anesthesiology, 12277Duke University, Durham, NC, USA.

Patients with traumatic brain injury (TBI) are at risk for extra-cranial complications, such as the acute respiratory distress syndrome (ARDS). We conducted an analysis of risk factors, mortality, and healthcare utilization associated with ARDS following isolated severe TBI. The National Trauma Data Bank (NTDB) dataset files from 2007-2014 were used to identify adult patients who suffered isolated [other body region-specific Abbreviated Injury Scale (AIS) < 3] severe TBI [admission total Glasgow Coma Scale (GCS) from 3 to 8 and head region-specific AIS >3]. In-hospital mortality was compared between patients who developed ARDS and those who did not. Utilization of healthcare resources (ICU length of stay, hospital length of stay, duration of mechanical ventilation, and frequency of tracheostomy and gastrostomy tube placement) was also examined. This retrospective cohort study included 38,213 patients with an overall ARDS occurrence of 7.5%. Younger age, admission tachycardia, pre-existing vascular and respiratory diseases, and pneumonia were associated with the development of ARDS. Compared to patients without ARDS, patients that developed ARDS experienced increased in-hospital mortality (OR 1.13, 95% CI 1.01-1.26), length of stay (p = <0.001), duration of mechanical ventilation (p = < 0.001), and placement of tracheostomy (OR 2.70, 95% CI 2.34-3.13) and gastrostomy (OR 2.42, 95% CI 2.06-2.84). After isolated severe TBI, ARDS is associated with increased mortality and healthcare utilization. Future studies should focus on both prevention and management strategies specific to TBI-associated ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0885066620972001DOI Listing
November 2020

Synergy between Wsp1 and Dip1 may initiate assembly of endocytic actin networks.

Elife 2020 11 12;9. Epub 2020 Nov 12.

Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, United States.

The actin filament nucleator Arp2/3 complex is activated at cortical sites in to assemble branched actin networks that drive endocytosis. Arp2/3 complex activators Wsp1 and Dip1 are required for proper actin assembly at endocytic sites, but how they coordinately control Arp2/3-mediated actin assembly is unknown. Alone, Dip1 activates Arp2/3 complex without preexisting actin filaments to nucleate 'seed' filaments that activate Wsp1-bound Arp2/3 complex, thereby initiating branched actin network assembly. In contrast, because Wsp1 requires preexisting filaments to activate, it has been assumed to function exclusively in propagating actin networks by stimulating branching from preexisting filaments. Here we show that Wsp1 is important not only for propagation but also for initiation of endocytic actin networks. Using single molecule total internal reflection fluorescence microscopy we show that Wsp1 synergizes with Dip1 to co-activate Arp2/3 complex. Synergistic co-activation does not require preexisting actin filaments, explaining how Wsp1 contributes to actin network initiation in cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.60419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707826PMC
November 2020

Individualized homeopathic medicines and Urtica urens mother tincture in treatment of hyperuricemia: an open, randomized, pragmatic, pilot trial.

J Complement Integr Med 2020 Oct 20. Epub 2020 Oct 20.

Howrah, West Bengal, India.

Objectives The quality of management of hyperuricemia has remained sub-optimal owing to unavoidable toxicities, limitations, and dearth of novel advances. Homeopathy has remained under-researched in hyperuricemia. We investigated the clinical effectiveness of three treatment regimens - individualized homeopathy (IH), Urtica urens mother tincture (UUMT), and both (IH + UUMT) along with lifestyle modifications in a sample of 90 patients with hyperuricemia. Methods An open, randomized (1:1:1), 3 parallel arms (IH, UUMT, and IH + UUMT), pragmatic trial was conducted at National Institute of Homoeopathy, Kolkata. Outcome measures were serum uric acid (primary), Gout Assessment Questionnaire version 2 (GAQ2, secondary), and Measure Yourself Medical Outcome Profile version 2 (MYMOP2, secondary); all measured at baseline, and after 3 and 6 months. Intention- to-treat sample was analyzed to detect group differences by unpaired t tests. Results Attrition rate was 8.9% (IH: 3, UUMT: 3, IH + UUMT: 2). Groups were comparable at baseline. Reductions in serum uric acid over 3 months were comparatively higher (p=0.057) in the UUMT group than others, however, the differences were narrowed over 6 months (p=0.119). Per protocol analysis of serum uric acid level revealed similar trend of significantly higher reduction in the UUMT group than the other two (3 months: p=0.001; 6 months: p=0.007). No significant differences existed in reductions of GAQ2 scores among the three groups. Few significant differences were detected in MYMOP scores over 3 months favoring IH against others (symptom 2, p=0.001 and wellbeing score, p=0.002), and also over 6 months favoring IH + UUMT against others (symptom 1, p<0.001). Conclusion Although all three therapies showed similar improvements, the IH + UUMT group had more positive direction of effects than IH or UUMT alone; however, no definite conclusion could be arrived at. Further trials are warranted with larger sample size. Trial registration: CTRI/2018/05/014026.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jcim-2020-0129DOI Listing
October 2020

Echocardiogram Utilization Patterns and Association With Mortality Following Severe Traumatic Brain Injury.

Anesth Analg 2021 04;132(4):1060-1066

Critical Care and Perioperative Epidemiologic Research (CAPER) Unit, Department of Anesthesiology.

Background: Severe traumatic brain injury (TBI) can result in left ventricular dysfunction, which can lead to hypotension and secondary brain injuries. Although echocardiography is often used to examine cardiovascular function in multiple clinical settings, its use and association with outcomes following severe TBI are not known. To address this gap, we used the National Trauma Data Bank (NTDB) to describe utilization patterns of echocardiography and examine its association with mortality following severe TBI.

Methods: A retrospective cohort study was conducted using a large administrative trauma registry maintained by the NTDB from 2007 to 2014. Patients >18 years with isolated severe TBI, and without concurrent severe polytrauma, were included in the study. We examined echocardiogram utilization patterns (including overall utilization, factors associated with utilization, and variation in utilization) and the association of echocardiography utilization with hospital mortality, using multivariable logistic regression models.

Results: Among 47,808 patients, echocardiogram was utilized as part of clinical care in 2548 patients (5.3%). Clinical factors including vascular comorbidities and hemodynamic instability were associated with increased use of echocardiograms. Nearly half (46.0%, 95% confidence interval [CI], 40.3%-51.7%) of the variation in echocardiogram utilization was explained at the individual hospital level, above and beyond patient and injury factors. Exposure to an echocardiogram was associated with decreased odds of in-hospital mortality following severe TBI (adjusted odds ratio [OR] = 0.77; 95% CI, 0.69-0.87; P < .001).

Conclusions: Echocardiogram utilization following severe TBI is relatively low, with wide variation in use at the hospital level. The association with decreased in-hospital mortality suggests that the information derived from echocardiography may be relevant to improving patient outcomes but will require confirmation in further prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1213/ANE.0000000000005110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878567PMC
April 2021

p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.

Cancer Res 2020 08 24;80(16):3251-3264. Epub 2020 Jun 24.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.

KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38γ MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38γ interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38γ increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38γ decreased PFKFB3 and GLUT2 expression. p38γ phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38γ decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38γ to stimulate glycolysis and PDAC growth and p38γ required PFKFB3/S467 to promote these activities. A p38γ inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38γ. Moreover, overexpression of p38γ, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38γ links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38γ and PFKFB3 may be targeted for therapeutic intervention in PDAC. SIGNIFICANCE: These findings show that p38γ links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38γ and PFKFB3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-3281DOI Listing
August 2020

The Magnitude of Blood Pressure Reduction Predicts Poor In-Hospital Outcome in Acute Intracerebral Hemorrhage.

Neurocrit Care 2020 10;33(2):389-398

Department of Neurology, San Camillo de' Lellis District General Hospital, Rieti, Italy.

Background: Early systolic blood pressure (SBP) reduction is believed to improve outcome after spontaneous intracerebral hemorrhage (ICH), but there has been a limited assessment of SBP trajectories in individual patients. We aimed to determine the prognostic significance of SBP trajectories in ICH.

Methods: We collected routine data on spontaneous ICH patients from two healthcare systems over 10 years. Unsupervised functional principal components analysis (FPCA) was used to characterize SBP trajectories over first 24 h and their relationship to the primary outcome of unfavorable shift on modified Rankin scale (mRS) at hospital discharge, categorized as an ordinal trichotomous variable (mRS 0-2, 3-4, and 5-6 defined as good, poor, and severe, respectively). Ordinal logistic regression models adjusted for baseline SBP and ICH volume were used to determine the prognostic significance of SBP trajectories.

Results: The 757 patients included in the study were 65 ± 23 years old, 56% were men, with a median (IQR) Glasgow come scale of 14 (8). FPCA revealed that mean SBP over 24 h and SBP reduction within the first 6 h accounted for 76.8% of the variation in SBP trajectories. An increase in SBP reduction (per 10 mmHg) was significantly associated with unfavorable outcomes defined as mRS > 2 (adjusted-OR = 1.134; 95% CI 1.044-1.233, P = 0.003). Compared with SBP reduction < 20 mmHg, worse outcomes were observed for SBP reduction = 40-60 mmHg (adjusted-OR = 1.940, 95% CI 1.129-3.353, P = 0.017) and > 60 mmHg, (adjusted-OR = 1.965, 95% CI 1.011, 3.846, P = 0.047). Furthermore, the association of SBP reduction and outcome varied according to initial hematoma volume. Smaller SBP reduction was associated with good outcome (mRS 0-2) in small (< 7.42 mL) and medium-size (≥ 7.42 and < 30.47 mL) hematomas. Furthermore, while the likelihood of good outcome was low in those with large hematomas (≥ 30.47 mL), smaller SBP reduction was associated with decreasing probability of severe outcome (mRS 5-6).

Conclusion: Our analyses suggest that in the first 6 h SBP reduction is significantly associated with the in-hospital outcome that varies with initial hematoma volume, and early SBP reduction > 40 mmHg may be harmful in ICH patients. For early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12028-020-01016-zDOI Listing
October 2020

Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.

Stroke 2020 07 10;51(7):2153-2160. Epub 2020 Jun 10.

Department of Neurology (A.B., S.U., A.R.-T., A.C., M.P., C.K., K.S., Z.D., S.M.G., A.V., M.E.G., C.D.A., J.R.), Massachusetts General Hospital, Boston.

Background And Purpose: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the () gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and genotype predict ICH recurrence. We then developed and validated a combined -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

Results: Cortical superficial siderosis, cerebral microbleed, and ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all <0.05). Combining genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

Conclusions: Combining MRI and genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.028310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311289PMC
July 2020

Characterizing distinct components of tactical aircraft noise sources.

J Acoust Soc Am 2020 May;147(5):3550

Blue Ridge Research and Consulting, LLC, Asheville, North Carolina 28801, USA.

Noise from a tactical aircraft can impact operations due to concerns regarding military personnel noise exposure and community annoyance and disturbance. The efficacy of mission planning can increase when the distinct, complex acoustic source mechanisms creating the noise are better understood. For each type of noise, equivalent acoustic source distributions are obtained from a tied-down F-35B operating at various engine conditions using the hybrid method for acoustic source imaging of Padois, Gauthier, and Berry [J. Sound Vib. 333, 6858-6868 (2014)]. The source distributions for the distinct noise types are obtained using different sections of a 71 element, ground-based linear array. Using a subarray close to the nozzle exit plane, source distributions are obtained for fine-scale turbulent mixing noise and broadband shock-associated noise, although grating lobes complicate interpretations at higher frequencies. Results for a subarray spanning the maximum sound region show that the multiple frequency peaks in tactical aircraft noise appear to originate from overlapping source regions. The observation of overlapping spatial extent of competing noise sources is supported by the coherence properties of the source distributions for the different subarrays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1121/10.0001260DOI Listing
May 2020

Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.

Nat Commun 2020 06 1;11(1):2739. Epub 2020 Jun 1.

Synlogic, Inc., 301 Binney street, suite 402, Cambridge, Massachusetts, 02142, United States.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16602-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264239PMC
June 2020

Modifiable Lifestyle Factors Associated With Response to Treatment in Early Rheumatoid Arthritis.

ACR Open Rheumatol 2020 Jun 26;2(6):371-377. Epub 2020 May 26.

Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.

Objective: We aimed to evaluate the associations between response to algorithm-directed treat-to-target conventional synthetic disease-modifying antirheumatic drug therapy and potentially modifiable lifestyle factors, including dietary fish oil supplementation, body mass index (BMI), and smoking history in a rheumatoid arthritis (RA) inception cohort.

Methods: Patients with RA with a duration of less than 12 months were reviewed every 3 to 6 weeks to adjust therapy according to disease response. All patients received advice to take fish oil supplements, and omega-3 status was measured as plasma levels of eicosapentaenoic acid (EPA). Lifestyle factors and other variables potentially prognostic for 28-joint Disease Activity Score (DAS28) remission and DAS28 low disease activity (LDA) at the 12-month visit were included in multivariable logistic regression models.

Results: Of 300 participants, 57.7% reached DAS28 LDA, and 43.7% were in DAS28 remission at 1 year. Increase in plasma EPA was associated with an increase in the odds of being in LDA (adjusted odds ratio [OR] = 1.27; P < 0.0001) and remission (adjusted OR = 1.21; P < 0.001). There was some evidence that the effect of BMI on LDA might be modified by smoking history. An increase in BMI was associated with a decrease in the odds of being in LDA in current and former smokers but had no impact on LDA in patients who had never smoked. There were no meaningful associations between BMI or smoking history and remission.

Conclusion: Omega-3 status, BMI, and smoking history are potential predictors of outcome in early RA. The possibility of an effect modification by smoking on the predictive value of BMI merits further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr2.11132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301874PMC
June 2020

Translational Neurocritical Care Research: Advancing Understanding and Developing Therapeutics.

Neurotherapeutics 2020 04;17(2):389-391

Departments of Anesthesiology and Neurology, Duke University, Durham, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-020-00867-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283417PMC
April 2020

Jellyfish distribution in space and time predicts leatherback sea turtle hot spots in the Northwest Atlantic.

PLoS One 2020 14;15(5):e0232628. Epub 2020 May 14.

Biology Department, Dalhousie University, Halifax, Nova Scotia, Canada.

Leatherback sea turtles (Dermochelys coriacea) migrate to temperate Canadian Atlantic waters to feed on gelatinous zooplankton ('jellyfish') every summer. However, the spatio-temporal connection between predator foraging and prey-field dynamics has not been studied at the large scales over which these migratory animals occur. We use 8903 tows of groundfish survey jellyfish bycatch data between 2006-2017 to reveal spatial jellyfish hot spots, and matched these data to satellite-telemetry leatherback data over time and space. We found highly significant overlap of jellyfish and leatherback distribution on the Scotian Shelf (r = 0.89), moderately strong correlations of jellyfish and leatherback spatial hot spots in the Gulf of St. Lawrence (r = 0.59), and strong correlations in the Bay of Fundy (r = 0.74), which supports much lower jellyfish density. Over time, jellyfish bycatch data revealed a slight northward range shift in the Gulf of St. Lawrence, consistent with gradual warming of these waters. Two-stage generalized linear modelling corroborated that sea surface temperature, year, and region were significant predictors of jellyfish biomass, suggesting a climate signal on jellyfish distribution, which may shift leatherback critical feeding habitat over time. These findings are useful in predicting dynamic habitat use for endangered leatherback turtles, and can help to anticipate large-scale changes in their distribution in response to climate-related changes in prey availability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232628PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224493PMC
August 2020

Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury.

Neurotherapeutics 2020 04;17(2):475-483

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

Over the last few decades, increasing evidence demonstrates that the neuroinflammatory response is a double-edged sword. Although overly robust inflammatory responses may exacerbate secondary tissue injury, inflammatory processes are ultimately necessary for recovery. Traditional drug discovery often relies on reductionist approaches to isolate and modulate specific intracellular pathways believed to be involved in disease pathology. However, endogenous brain proteins are often pleiotropic in order to regulate neuroinflammation and recovery mechanisms. Thus, a process of "backward translation" aims to harness the adaptive properties of endogenous proteins to promote earlier and greater recovery after acute brain injury. One such endogenous protein is apolipoprotein E (apoE), the primary apolipoprotein produced in the brain. Robust preclinical and clinical evidence demonstrates that endogenous apoE produced within the brain modulates the neuroinflammatory response of the acutely injured brain. Thus, one innovative approach to improve outcomes following acute brain injury is administration of exogenous apoE-mimetic drugs optimized to cross the blood-brain barrier. In particular, one promising apoE mimetic peptide, CN-105, has demonstrated efficacy across a wide variety of preclinical models of brain injury and safety and feasibility in early-phase clinical trials. Preclinical and clinical evidence for apoE's neuroprotective effects and downregulation of neuroinflammatory and the resulting translational therapeutic development strategy for an apoE-based therapeutic are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-020-00858-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283431PMC
April 2020

Author Correction: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

Sci Rep 2020 Apr 20;10(1):6898. Epub 2020 Apr 20.

Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-63178-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170870PMC
April 2020

Selective Serotonin Reuptake Inhibitors and Intracerebral Hemorrhage Risk and Outcome.

Stroke 2020 04 4;51(4):1135-1141. Epub 2020 Mar 4.

Department of Neurology (S.S., M.L.J.), Duke University, Durham, NC.

Background and Purpose- Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre-intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods- Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed "continuous"), and post-ICH only (termed "new"). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models. Results- The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632-1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162-2.408]; =0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance (=0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301-0.875]; =0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group. Conclusions- In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01202864.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.028406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147963PMC
April 2020

Oral Methylphenidate Treatment of an Adolescent ADHD Rat Model Does Not Alter Cocaine-Conditioned Place Preference during Adulthood: A Negative Report.

J Psychiatr Brain Sci 2019 30;4. Epub 2019 Dec 30.

Department of Psychiatry and Behavioral Sciences, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

The stimulant, methylphenidate (MPH), is commonly used to treat attention deficit hyperactivity disorder (ADHD) and has been increasingly prescribed for school age children and adolescents. Concerns regarding its long-term effects on later substance use disorders (SUDs) have been raised. Previous animal studies have produced contradictory results regarding whether early exposure to MPH increases or protects against SUD in adulthood. The goal of our study was to determine if clinically relevant doses of MPH during adolescence alter cocaine responsiveness in adulthood in a rat model of ADHD, the spontaneous hypertensive rat (SHR). We pretreated SHRs with saline or MPH (2.5 mg/kg once or twice day) via oral gavage during their dark cycle from postnatal day 35 (p35) to p44. Adult rats (p80) were assessed in an eight-session cocaine-conditioned place preference test (CPP). Four doses of cocaine were administered via intraperitoneal injection (i.p.) during the conditioning sessions: 1, 5, 10 and 20 mg/kg. Once per day MPH treatment had a small sensitizing effect on baseline general locomotor activity in a novel environment at p80 as well as a limited suppressive effect on reward-specific locomotor activity as measured by the decreased preference to enter the cocaine-paired chamber. This treatment did not have any effect on the amount of time that rats chose to spend in the cocaine-paired chamber. Twice per day MPH treatment had no effect on locomotion or drug-preference. Our results suggest that MPH treatment of ADHD rats during adolescence does not alter preference for cocaine in adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20900/jpbs.20190021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953993PMC
December 2019

Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease.

Neurobiol Dis 2020 03 16;136:104712. Epub 2019 Dec 16.

Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2019.104712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026836PMC
March 2020

Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).

J Med Chem 2019 12 25;62(24):11004-11018. Epub 2019 Nov 25.

Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P.R. China.

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b01295DOI Listing
December 2019

Single-nucleotide polymorphism rs13426236 contributes to an increased prostate cancer risk via regulating MLPH splicing variant 4.

Mol Carcinog 2020 01 29;59(1):45-55. Epub 2019 Oct 29.

Department of Pathology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

A prostate cancer risk single-nucleotide polymorphism (SNP), rs13426236, is significantly associated with melanophilin (MLPH) expression. To functionally characterize role of the rs13426236 in prostate cancer, we first performed splicing-specific expression quantitative trait loci analysis and refined the significant association of rs13426236 allele G with an increased expression of MLPH splicing transcript variant 4 (V4) (P = 7.61E-5) but not other protein-coding variants (V1-V3) (P > .05). We then performed an allele-specific reporter assay to determine if SNP-containing sequences functioned as an active enhancer. Compared to allele A, allele G of rs13426236 showed significantly higher luciferase activity on the promoter of the splicing transcript V4 (P < .03) but not on the promoter of transcript V1 (P > .05) in two prostate cancer cell lines (DU145 and 22Rv1). Cell transfection assays showed stronger effect of transcript V4 than V1 on promoting cell proliferation, invasion, and antiapoptotic activities. RNA profiling analysis demonstrated that transcript V4 overexpression caused significant expression changes in glycosylation/glycoprotein and metal-binding gene ontology pathways (FDR < 0.01). We also found that both transcripts V4 and V1 were significantly upregulated in prostate adenocarcinoma (P ≤ 2.49E-6) but only transcript V4 upregulation was associated with poor recurrence-free survival (P = .028, hazard ratio = 1.63, 95% confidence interval = 1.05-2.42) in The Cancer Genome Atlas data. This study provides strong evidence showing that prostate cancer risk SNP rs13426236 upregulates expression of MLPH transcript V4, which may function as a candidate oncogene in prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.23127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219604PMC
January 2020