Publications by authors named "Michael Davidson"

762 Publications

Mammospheres of letrozole-resistant breast cancer cells enhance breast cancer aggressiveness.

Oncol Lett 2021 Aug 28;22(2):620. Epub 2021 Jun 28.

Division of Basic Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.

Aromatase inhibitors (AIs), such as letrozole, are considered as first-line treatment for estrogen receptor-positive breast cancer in postmenopausal women. Despite the successful use of letrozole, resistance to therapy, tumor relapse and metastasis remain principal causes of patient mortality. Although there is no therapy currently available for AI-resistant breast cancer, previous reports have demonstrated that AI resistance is associated with hormone independence, increased growth factor signaling, enhanced cellular motility and epithelial to mesenchymal transition (EMT). This suggests a convergence of EMT and cancer stem cells (CSCs) in endocrine resistance. The present study evaluated the contribution of mammospheres in letrozole-resistant breast cancer by characterizing mammospheres and their potential impact on cellular motility. Ovariectomized immunocompromised female mice were inoculated in the mammary fat pad with either letrozole-resistant MCF-7 cells (LTLT-Ca) or letrozole-sensitive MCF-7 cells (AC-1). Subsequently, intratumoral CSC marker expression was assessed by immunohistochemistry. The results indicated that LTLT-Ca tumors were CD44/CD24, while AC-1 tumors presented low CD44/CD24 expression. Since mammosphere formation depends on CSCs, both cell lines were cultured either adherently (2D) or as mammospheres (3D) to assess the CD44/CD24 protein expression profile. When 3D culturing both cell lines, higher expression levels of CD44 and CD24 were observed when compared with their adherent counterparts, with the most robust change observed in the LTLT-Ca cell line. To quantitate the breast cancer stem cell activity, mammosphere formation assays were performed, and the LTLT-Ca cells formed mammospheres at a 3.4-fold higher index compared with AC-1 cells. Additionally, targeted gene expression arrays were conducted to compare the LTLT-Ca 3D and 2D cells, revealing that LTLT-Ca 3D cells displayed decreased expression levels of genes involved in cell adhesion and tumor suppression (e. g., E-cadherin, caveolin 1 and β-catenin). To validate this finding, wound healing assays were performed, and LTLT-Ca mammospheres exhibited a 70% wound closure, whereas AC-1 mammospheres exhibited a 39% wound closure. Collectively, the present findings demonstrated a strong association between AI-resistant mammospheres and an increased propensity for migration, which may be indicative of a poor prognosis.
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http://dx.doi.org/10.3892/ol.2021.12881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258623PMC
August 2021

Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs.

Am J Psychiatry 2021 Jul 14:appiajp202020111657. Epub 2021 Jul 14.

Stanley Medical Research Institute, Kensington, Md. (Weiser); Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel (Weiser, Levi); Department of Psychiatry, Tel Aviv University, Ramat Aviv, Israel (Weiser); Department of Psychiatry, University of Illinois, Chicago (Davis); VA Capitol Healthcare Network (VISN 5) Mental Illness Research, Education, and Clinical Center (MIRECC), Baltimore (Brown, Medoff, Kreyenbuhl); Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore (Brown; Medoff, Kreyenbuhl); Johns Hopkins School of Nursing, Baltimore (Slade); Department of Psychiatry, Division of Psychiatric Services Research, University of Maryland School of Medicine, Baltimore (Fang); Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore (Buchanan); and University of Nicosia Medical School, Nicosia, Cyprus (Davison).

Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system.

Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group.

Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine.

Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.
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http://dx.doi.org/10.1176/appi.ajp.2020.20111657DOI Listing
July 2021

Telemedicine at the Joint Readiness Training Center: Expanding Forward Medical Capability.

Med J (Ft Sam Houst Tex) 2021 Apr-Jun(PB 8-21-04/05/06):9-13

Joint Readiness Training Center, Ft. Polk, LA.

Introduction: The US Army's transition from counterinsurgency operations to preparation for large-scale combat operations is likely to bring unique access to care challenges on the battlefield. Ruggedized computer systems exist that allow forward medical personnel to establish telehealth connections with rear-based specialists. We describe our use of one such device during simulated force on force operations at the Joint Readiness Training Center (JRTC).

Methods: Our infantry brigade combat team brought a telehealth device to JRTC 20-02. The device comprised a mobile laptop and peripheral medical devices. We used the Warfighter Information Network-Tactical Increment 2 Tactical Communications Node (TCN) to establish communication between the device and external entities. We sought to establish connectivity in the Fort Polk, LA, cantonment area as part of reception, staging, onward movement, and integration operations.

Results: We successfully executed video calls from the field utilizing the telehealth device at the JRTC rear aid station and the local military treatment facility on Fort Polk, LA. We also executed calls to our home station military treatment facility on Fort Carson, CO. Each of these calls lasted approximately five minutes with sustained high-quality video and audio feeds.

Conclusions: Our experience provides proof of concept that telehealth may enable rear-based medical personnel to expand the medical capabilities of medics based forward in the battlespace. Telehealth devices may prove feasible for use with strictly tactical communications architecture in the kinetic setting of large scale combat operations.
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July 2021

Identifying an elusive target with the help of an unproven technique.

Mol Psychiatry 2021 Jul 9. Epub 2021 Jul 9.

Nicosia University School of Medicine, Nicosia, Cyprus.

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http://dx.doi.org/10.1038/s41380-021-01213-yDOI Listing
July 2021

The effects of JNJ-39393406 a positive allosteric nicotine modulator on mood and cognition in patients with unipolar depression: A double-blind, add-on, placebo-controlled trial.

Eur Neuropsychopharmacol 2021 May 20;51:33-42. Epub 2021 May 20.

Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Nicotinic agonists have been shown to improve cognition and mood, but this improvement is inconsistent and short-lived, possibly due to receptor desensitization. Positive Allosteric Modulators (PAMs) of the nicotinic alpha-7 nicotinic-acetyl-choline receptor (a7nAChR) are hypothesized to change the configuration of the nicotinic receptor and delay desensitization, potentially increasing the duration of the activation of the receptor, and improving clinical efficacy. This was a randomized controlled trial (RCT) adding JNJ-39393406 9 (a PAM of the a7nAChR) (n=35) or placebo (n=36) to treatment as usual for two weeks in 71 patients with unipolar depression. Mixed models for repeated measures analyses were performed Primary outcome measures were the Brief Assessment of Cognition in Schizophrenia (BACS) composite and the Montgomery-Asperg Depression Rating Scale (MADRS) scores. The drug was well tolerated, however mixed models for repeated measures comparing JNJ-39393406 to placebo showed no significant difference for MADRS total score (p=0.78), BACS composite score (p=0.34), or any of the secondary outcome measures. There was no significant difference in adverse events between the study groups (p=0.44). In conclusion, this study's findings do not support the hypothesis that a positive nicotinic receptor modulator can improve cognitive or depressive symptomatology in patients with unipolar depression.
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http://dx.doi.org/10.1016/j.euroneuro.2021.04.020DOI Listing
May 2021

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.

Lancet 2021 May 17;397(10289):2060-2069. Epub 2021 May 17.

Corvidia Therapeutics, Waltham, MA, USA.

Background: IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction.

Methods: RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117.

Findings: Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia.

Interpretation: Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease.

Funding: Novo Nordisk.
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http://dx.doi.org/10.1016/S0140-6736(21)00520-1DOI Listing
May 2021

Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial.

JAMA Cardiol 2021 May 16. Epub 2021 May 16.

Monash Cardiovascular Research Centre, Melbourne, Victoria, Australia.

Importance: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes.

Objective: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo.

Design, Setting, And Participants: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020).

Interventions: Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil.

Main Outcomes And Measures: The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization.

Results: Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 μg/mL (interquartile range [IQR], 46-131 μg/mL) for EPA and 91 μg/mL (IQR, 71-114 μg/mL) for DHA with top tertile levels of 151 μg/mL (IQR, 132-181 μg/mL) and 118 μg/mL (IQR, 102-143 μg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results.

Conclusions And Relevance: Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.
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http://dx.doi.org/10.1001/jamacardio.2021.1157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126992PMC
May 2021

Safety monitoring of two and four-weekly adjuvant durvalumab for patients with stage III NSCLC: implications for the COVID-19 pandemic and beyond.

Lung Cancer 2021 06 30;156:147-150. Epub 2021 Apr 30.

Lung Unit, Department of Medical Oncology, The Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK; The Drug Development Unit, The Royal Marsden Hospital/Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK. Electronic address:

Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086258PMC
June 2021

Misreporting of Results of Research in Psychiatry.

Schizophr Bull 2021 Aug;47(5):1254-1260

Stanley Medical Research Institute, Kensington, MD, USA.

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.
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http://dx.doi.org/10.1093/schbul/sbab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379531PMC
August 2021

The future of nurse education? Studying at the Open University in Scotland.

Br J Nurs 2021 Apr;30(7):428-432

Senior Lecturer in Children and Young People's Nursing, Faculty of Wellbeing, Education and Language Studies, The Open University, Edinburgh.

This article describes nurse education with the Open University in Scotland (OUiS). Although there are problems with nurse recruitment and retention across the UK, in Scotland the landscape is somewhat different, with greater support for students required in remote and rural areas. Despite these challenges, the OUiS continues to recruit to the commissioned numbers of places. OUiS nursing students are primarily health care support workers who are a key group within the health and social care workforce but historically have faced many challenges in developing clear career pathways into nursing. At the heart of the OU is the fundamental recognition of distance online pedagogy, complemented by work-based learning support by employers. Partnership working between the OU, employers and education commissioners is crucial to its success.
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http://dx.doi.org/10.12968/bjon.2021.30.7.428DOI Listing
April 2021

Quantitative Proteomic Profiling Identifies a Potential Novel Chaperone Marker in Resistant Breast Cancer.

Front Oncol 2021 25;11:540134. Epub 2021 Feb 25.

Division of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States.

Development of aromatase inhibitor resistant breast cancer among postmenopausal women continues to be a major clinical obstacle. Previously, our group demonstrated that as breast cancer cells transition from hormone-dependent to hormone-independent, they are associated with increased growth factor signaling, enhanced cellular motility, and the epithelial to mesenchymal transition (EMT). Given the complexity of cancer stem cells (CSC) and their implications on endocrine resistance and EMT, we sought to understand their contribution towards the development of aromatase inhibitor resistant breast cancer. Cells cultured three dimensionally as mammospheres are enriched for CSCs and more accurately recapitulates tumors . Therefore, a global proteomic analysis was conducted using letrozole resistant breast cancer cells (LTLT-Ca) mammospheres and compared to their adherent counterparts. Results demonstrated over 1000 proteins with quantitative abundance ratios were identified. Among the quantified proteins, 359 were significantly altered ( < 0.05), where 173 were upregulated and 186 downregulated ( < 0.05, fold change >1.20). Notably, midasin, a chaperone protein required for maturation and nuclear export of the pre-60S ribosome was increased 35-fold. Protein expression analyses confirmed midasin is ubiquitously expressed in normal tissue but is overexpressed in lobular and ductal breast carcinoma tissue as well as ER+ and ER- breast cancer cell lines. Functional enrichment analyses indicated that 19 gene ontology terms and one KEGG pathway were over-represented by the down-regulated proteins and both were associated with protein synthesis. Increased midasin was strongly correlated with decreased relapse free survival in hormone independent breast cancer. For the first time, we characterized the global proteomic signature of CSC-enriched letrozole-resistant cells associated with protein synthesis, which may implicate a role for midasin in endocrine resistance.
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http://dx.doi.org/10.3389/fonc.2021.540134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951058PMC
February 2021

Acute day units for mental health crises: a qualitative study of service user and staff views and experiences.

BMC Psychiatry 2021 03 10;21(1):146. Epub 2021 Mar 10.

Division of Psychiatry, UCL, 149 Tottenham Court Road, London, W1T 7NF, UK.

Background: Acute Day Units (ADUs) provide intensive, non-residential, short-term treatment for adults in mental health crisis. They currently exist in approximately 30% of health localities in England, but there is little research into their functioning or effectiveness, and how this form of crisis care is experienced by service users. This qualitative study explores the views and experiences of stakeholders who use and work in ADUs.

Methods: We conducted 36 semi-structured interviews with service users, staff and carers at four ADUs in England. Data were analysed using thematic analysis. Peer researchers collected data and contributed to analysis, and a Lived Experience Advisory Panel (LEAP) provided perspectives across the whole project.

Results: Both service users and staff provided generally positive accounts of using or working in ADUs. Valued features were structured programmes that provide routine, meaningful group activities, and opportunities for peer contact and emotional, practical and peer support, within an environment that felt safe. Aspects of ADU care were often described as enabling personal and social connections that contribute to shifting from crisis to recovery. ADUs were compared favourably to other forms of home- and hospital-based acute care, particularly in providing more therapeutic input and social contact. Some service users and staff thought ADU lengths of stay should be extended slightly, and staff described some ADUs being under-utilised or poorly-understood by referrers in local acute care systems.

Conclusions: Multi-site qualitative data suggests that ADUs provide a distinctive and valued contribution to acute care systems, and can avoid known problems associated with other forms of acute care, such as low user satisfaction, stressful ward environments, and little therapeutic input or positive peer contact. Findings suggest there may be grounds for recommending further development and more widespread implementation of ADUs to increase choice and effective support within local acute care systems.
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http://dx.doi.org/10.1186/s12888-021-03140-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944597PMC
March 2021

The clinical black, white, and gray lessons.

Curr Opin Lipidol 2021 04;32(2):151-156

Preventive Cardiology, Section of Cardiology, The University of Chicago Medicine, Chicago, Illinois, USA.

Purpose Of Review: This review examines recent contradictory large, well-controlled randomized control trials assessing the effects of omega-3 fatty acids and colchicine on cardiovascular (CV) outcomes.

Recent Findings: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with Epanova in high Cardiovascular Risk patients with Hypertriglyceridemia (STRENGTH) trial assessed the CV outcomes using high-dose omega-3 fatty acids in statin-treated patients with moderate hypertriglyceridemia and high-risk for CV disease with differing results. Similarly, Colchicine Cardiovascular Outcomes trial, (COLCOT) second Low Dose Colchicine (LoDoCo2), and Colchicine in patients with Acute Coronary Syndrome (COPS) assessed the CV outcomes using low-dose colchicine in patients with coronary artery disease with inconsistent results. These contradictory findings among studies assessing similar questions with the same drug or a drug within the same class challenge the scientific validity and clinical applicability of the derived conclusions.

Summary: A comprehensive review revealed many differences between the trials, which could have contributed to observed divergent results. Consistent findings across multiple trials help strengthen the evidence for specific endpoints or sub-populations, and these findings must be included in guidelines. Large prospective cohort studies with diligent study protocols are warranted in the future to resolve unanswered dilemmas.
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http://dx.doi.org/10.1097/MOL.0000000000000745DOI Listing
April 2021

Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade.

Anticancer Res 2021 Feb;41(2):583-599

Division of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.;

Background/aim: Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).

Materials And Methods: To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted.

Results: MAP3K6 was up-regulated in the T47DaromLR cells by 3.2-fold (p<0.01) which was associated with a decrease in relapse-free survival among breast cancer patients (p=0.0019). Members of the MAPK/p38 pathway (i.e., phospho-MKK6, phospho-p38, phospho-RSK1, phospho-RSK2, and p70S6K MAPK) were also increased in the T47DaromLR cells, while inhibiting p38 led to decreased proliferation and induction of apoptosis.

Conclusion: Activation of the p38/MAPK pathway leads to ER+ AI-resistance.
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http://dx.doi.org/10.21873/anticanres.14810DOI Listing
February 2021

Adjunctive Aspirin vs Placebo in Patients With Schizophrenia: Results of Two Randomized Controlled Trials.

Schizophr Bull 2021 07;47(4):1077-1087

Department of Psychiatry, University of Illinois, Chicago, IL.

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was -3.9 (95% CI: -8.4 to 0.5, P = .10, effect size (ES) = -0.25) and at 8 weeks was -3.5 (95% CI: -7.5 to 0.5, P = .11, ES = -0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: -4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: -1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was -2.9 (95% CI: -6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.
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http://dx.doi.org/10.1093/schbul/sbaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266648PMC
July 2021

Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm - 2020 Executive Summary.

Endocr Pract 2020 Oct;26(10):1196-1224

Director, Adult Type 1 Diabetes Program, Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center, Columbus, Ohio.

The treatment of lipid disorders begins with lifestyle therapy to improve nutrition, physical activity, weight, and other factors that affect lipids. Secondary causes of lipid disorders should be addressed, and pharmacologic therapy initiated based on a patient's risk for atherosclerotic cardiovascular disease (ASCVD). Patients at extreme ASCVD risk should be treated with high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol (LDL-C) of <55 mg/dL, and those at very high ASCVD risk should be treated to achieve LDL-C <70 mg/dL. Treatment for moderate and high ASCVD risk patients may begin with a moderate-intensity statin to achieve an LDL-C <100 mg/dL, while the LDL-C goal is <130 mg/dL for those at low risk. In all cases, treatment should be intensified, including the addition of other LDL-C-lowering agents (i.e., proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, colesevelam, or bempedoic acid) as needed to achieve treatment goals. When targeting triglyceride levels, the desirable goal is <150 mg/dL. Statin therapy should be combined with a fibrate, prescription-grade omega-3 fatty acid, and/or niacin to reduce triglycerides in all patients with triglycerides ≥500 mg/dL, and icosapent ethyl should be added to a statin in any patient with established ASCVD or diabetes with ≥2 ASCVD risk factors and triglycerides between 135 and 499 mg/dL to prevent ASCVD events. Management of additional risk factors such as elevated lipoprotein(a) and statin intolerance is also described.
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http://dx.doi.org/10.4158/CS-2020-0490DOI Listing
October 2020

How I treat statin-associated side effects in an outpatient setting.

Future Cardiol 2021 Jan 19. Epub 2021 Jan 19.

Preventive Cardiology, Section of Cardiology, The University of Chicago, 5841 S Maryland Avenue, MC 6080 B-608A, Chicago, IL 60637, USA.

Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity. The most common side effect is statin-associated muscle symptoms. Uncommon side effects include new-onset diabetes mellitus and elevation in liver enzymes. These effects can lead to noncompliance and premature discontinuation of the medication. Hence, it is crucial to identify patients with true statin-associated side effects (SASE) to ensure optimal statin use. The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of SASE. In patients with true SASE, timely intervention with modified statin or non-statins is beneficial. Herein, we discuss key clinical trial data on statins and non-statins, and describe our center's approach toward patients with SASE.
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http://dx.doi.org/10.2217/fca-2020-0153DOI Listing
January 2021

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

J Am Soc Nephrol 2021 01 3;32(1):211-222. Epub 2020 Dec 3.

Corvidia Therapeutics, Inc., Waltham, Massachusetts.

Background: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation.

Methods: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies.

Results: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin.

Conclusions: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy.

Clinical Trial Registry Name And Registration Number: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.
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http://dx.doi.org/10.1681/ASN.2020050595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894678PMC
January 2021

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.

JAMA 2020 12;324(22):2268-2280

Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk.

Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk.

Design, Setting, And Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa.

Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins.

Main Outcomes And Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%).

Conclusions And Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.
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http://dx.doi.org/10.1001/jama.2020.22258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667577PMC
December 2020

Recent advances and emerging therapies in management of dyslipidemias.

Trends Cardiovasc Med 2020 Aug 25. Epub 2020 Aug 25.

Preventive Cardiology, Department of Cardiology, The University of Chicago Pritzker School of Medicine, Chicago 60637, IL, USA. Electronic address:

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide that have been shown to have a strong association with dyslipidemia. Despite efficacious LDL-C lowering therapies, there is evidence of residual CVD risk prompting a need for a novel approach to mitigate CVD. This review aims to provide a comprehensive overview of recent and emerging therapies for various dyslipidemias.
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http://dx.doi.org/10.1016/j.tcm.2020.08.007DOI Listing
August 2020

Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis.

Curr Atheroscler Rep 2020 07 25;22(9):48. Epub 2020 Jul 25.

Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA.

Purpose Of Review: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications.

Recent Findings: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.
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http://dx.doi.org/10.1007/s11883-020-00867-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381416PMC
July 2020

Do DSM classifications help or hinder
drug development?
.

Dialogues Clin Neurosci 2020 03;22(1):73-79

Assistant Professor University of Medicine 
Pharmacy Science and Technology Targu Mureş, Romania.

Development and regulatory approval of psychotropic drugs targets individuals with syndromes described in the current Diagnostic and Statistical Manual of Mental Disorders (DSM). This helps drug developers and regulators to communicate with prescribers, and prescribers to match a specific psychotropic with the individual patient(s) most likely to benefit from it. However, this practice has been criticized on the grounds that DSM syndromes are too heterogenous biologically, and the effects of psychotropics are too nonspecific to allow for an effective match. This review considers the advantages and disadvantages of the current practice and the possible alternatives. It concludes that efforts should be made to explore psychotropic development transdiagnostically, free of the DSM boundaries. However, currently there exists no alternative diagnostic system that is clearly superior to the DSM in terms of communications between the stakeholders in drug development.
.
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http://dx.doi.org/10.31887/DCNS.2020.22.1/mdavidsonDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365297PMC
March 2020

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Circ Res 2020 09 14;127(8):1094-1108. Epub 2020 Jul 14.

From the Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center (M.T.D., P.A.G., J.A.D., K.H.F.-W., T.M.N., T.R.K., D.M.M.), Duke University Medical Center, Durham, NC.

Rationale: Circumstantial evidence links the development of heart failure to posttranslational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse.

Objective: This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism.

Methods And Results: A DKO (dual knockout) mouse line with deficiencies in CrAT (carnitine acetyltransferase) and Sirt3 (sirtuin 3)-enzymes that oppose Kac by buffering the acetyl group pool and catalyzing lysine deacetylation, respectively-was developed to model extreme mitochondrial Kac in cardiac muscle, as confirmed by quantitative acetyl-proteomics. The resulting impact on mitochondrial bioenergetics was evaluated using a respiratory diagnostics platform that permits comprehensive assessment of mitochondrial function and energy transduction. Susceptibility of DKO mice to heart failure was investigated using transaortic constriction as a model of cardiac pressure overload. The mitochondrial acetyl-lysine landscape of DKO hearts was elevated well beyond that observed in response to pressure overload or Sirt3 deficiency alone. Relative changes in the abundance of specific acetylated lysine peptides measured in DKO versus Sirt3 KO hearts were strongly correlated. A proteomics comparison across multiple settings of hyperacetylation revealed ≈86% overlap between the populations of Kac peptides affected by the DKO manipulation as compared with experimental heart failure. Despite the severity of cardiac Kac in DKO mice relative to other conditions, deep phenotyping of mitochondrial function revealed a surprisingly normal bioenergetics profile. Thus, of the >120 mitochondrial energy fluxes evaluated, including substrate-specific dehydrogenase activities, respiratory responses, redox charge, mitochondrial membrane potential, and electron leak, we found minimal evidence of oxidative insufficiencies. Similarly, DKO hearts were not more vulnerable to dysfunction caused by transaortic constriction-induced pressure overload.

Conclusions: The findings challenge the premise that hyperacetylation per se threatens metabolic resilience in the myocardium by causing broad-ranging disruption to mitochondrial oxidative machinery.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317293DOI Listing
September 2020

Inflammation product effects on dilatational mechanics can trigger the Laplace instability and acute respiratory distress syndrome.

Soft Matter 2020 Jul;16(29):6890-6901

Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota, USA.

In the lungs, the Laplace pressure, ΔP = 2γ/R, would be higher in smaller alveoli than larger alveoli unless the surface tension, γ decreases with alveolar interfacial area, A, such that 2ε > γ in which ε = A(dγ/dA) is the dilatational modulus. In Acute Respiratory Distress Syndrome (ARDS), lipase activity due to the immune response to an underlying trauma or disease causes single chain lysolipid concentrations to increase in the alveolar fluids via hydrolysis of double-chain phospholpids in bacterial, viral, and normal cell membranes. Increasing lysolipid concentrations decrease the dilatational modulus dramatically at breathing frequencies if the soluble lysolipid has sufficient time to diffuse off the interface, causing 2ε < γ, thereby potentially inducing the "Laplace Instability", in which larger alveoli have a lower internal pressure than smaller alveoli. This can lead to uneven lung inflation, alveolar flooding, and poor gas exchange, typical symptoms of ARDS. While the ARDS lung contains a number of lipid and protein species in the alveolar fluid in addition to lysolipids, the surface activity and frequency dependent dilatational modulus of lysolipid suggest how inflammation may lead to the lung instabilities associated with ARDS. At high frequencies, even at high lysolipid concentrations, 2ε - γ > 0, which may explain the benefits ARDS patients receive from high frequency oscillatory ventilation.
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http://dx.doi.org/10.1039/d0sm00415dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462632PMC
July 2020

Schizotypal traits and neuropsychological performance: The role of processing speed.

Schizophr Res 2020 09 4;223:128-134. Epub 2020 Jul 4.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.

Background: Cognitive deficits, particularly in processing speed, are widely recognized as a critical feature of schizophrenia, and are also present across schizophrenia spectrum disorders. A number of important confounders, however, such as hospitalization effects and antipsychotic medication, have been shown to affect processing speed, causing debate as to the core cognitive deficits of schizophrenia. The study of individuals who are not clinically psychotic but have schizotypal traits allows investigation of cognitive deficits associated with both positive and negative schizotypy dimensions while excluding potential confounds.

Methods: A population-based community sample of 242 healthy adult volunteers assessed using the Structured Interview of Schizotypy - Revised (SIS-R) scale, and a neuropsychological testing battery that included measures of verbal ability, visual and verbal memory, verbal fluency, working memory, executive functions and processing speed. Participants were classified in High or Low Positive Schizotypy (H-PST or L-PST), High or Low Paranoia-like traits (H-PAR or L-PAR) and High or Low Negative Schizotypy (H-NST or L-NST) groups, respectively.

Results: Individuals with H-PST performed significantly (p < 0.05) worse than L-PST on measures of processing speed and executive functions. Processing speed deficits were also observed in individuals with H-PAR compared to L-PAR (p < 0.05). There were no statistically significant differences in neuropsychological performance between H-NST and L-NST on any measure.

Conclusions: In a population-based community sample, individuals with high positive schizotypal traits or paranoia-like traits show impairments in processing speed. Consistent with a dimensional view of psychosis, this supports the hypothesis that processing speed represents a core deficit of schizophrenia-like mental states.
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http://dx.doi.org/10.1016/j.schres.2020.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704687PMC
September 2020

Suspected Spontaneous Aqueous Humor Misdirection Syndrome in a Boston Terrier.

Case Rep Vet Med 2020 19;2020:1092562. Epub 2020 May 19.

Comparative Ophthalmology, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA.

An eight-year-old female spayed Boston Terrier presented to the North Carolina Veterinary Hospital with glaucoma in the left eye (OS). Initial ophthalmic examination revealed moderate ocular hypertension, a diffusely and markedly shallow anterior chamber with anteriorly displaced iris and lens, vitreal prolapse, and a normal iridocorneal angle (ICA) morphology. The patient displayed a paradoxical response to topical latanoprost with an increase in intraocular pressure. These examination findings led to a putative diagnosis of spontaneous aqueous humor misdirection syndrome (AHMS). The patient was successfully managed with topical carbonic anhydrase inhibitors (CAIs) and apraclonidine for eight months until progressive ulcerative keratitis necessitated enucleation of the affected globe. Histopathology and high-field magnetic resonance imaging (MRI) of the enucleated globe did not identify an underlying cause for the glaucoma. This case suggests that AHMS should be considered in dogs presenting with a shallow anterior chamber, vitreal prolapse, increased intraocular pressure, and no other causes of glaucoma.
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http://dx.doi.org/10.1155/2020/1092562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275946PMC
May 2020

Do Patterns of Instability or Severity of Psychopathology During Screening Predict Relapse in Schizophrenic Outpatient Subjects with Moderate to Severe Negative Symptoms Assigned to Placebo?

Innov Clin Neurosci 2020 Jan;17(1-3):27-29

Dr. Daniel is with Signant Health in Mclean, Virginia.

Patients with schizophrenia who, prior to inclusion in placebo-controlled trials, experience the most severe and/or unstable symptoms might be more likely to manifest symptomatic worsening upon antipsychotic discontinuation. This retrospective analysis included all randomized patients assigned to placebo (n=83) in a 12-week, double-blind, placebo-controlled outpatient trial of MIN-101 (roluperidone) for the treatment of negative symptoms in schizophrenia. The following risk factors were defined for exacerbation: instability between screening and baseline defined operationally as patients with the highest 10 percent of absolute change from the screening visit to baseline in the Positive and Negative Syndrome Scale (PANSS) total or one of the five PANSS Marder factors; screening or baseline severity in PANSS total or one of the five PANSS Marder factors; and gender and age. We used two operational criteria of relapse and the odds ratios of meeting the relapse criteria were calculated for each risk factor. The odds of meeting one of the operational thresholds for relapse after antipsychotic discontinuation were not statistically significantly increased in the subjects who were unstable on the PANSS total or on one of the five PANSS Marder factors before antipsychotic discontinuation. Further, the severity of PANSS total and Marder factor scores at screening and baseline were not statistically significantly associated with odds of relapse. Neither age nor gender had any effect on relapse rates. Mild to moderate symptomatic variations in the severity of symptoms during screening and more severe symptomology at baseline as measured by the PANSS were not predictive of increased risk of subsequent relapse in schizophrenic patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239560PMC
January 2020

Transport of Flexible, Oil-Soluble Diblock and BAB Triblock Copolymers to Oil/Water Interfaces.

Langmuir 2020 Jul 25;36(26):7227-7235. Epub 2020 Jun 25.

Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States.

The connection between block copolymer architecture and adsorption at fluid/fluid interfaces is poorly understood. We characterize the interfacial properties of a well-defined series of polyethylene oxide/polydimethyl siloxane (PDMS) diblock and BAB triblock copolymers at the dodecane/water interface. They are oil-soluble and quite flexible because of their hydrophobic PDMS block. Rather than relying on equilibrium interfacial measurements for which it is difficult to mitigate experimental uncertainty during adsorption, we combine measurements of steady-state adsorption, dilatational rheology, and adsorption/desorption dynamics. Steady-state interfacial pressure is insensitive to interfacial curvature and mostly agrees with theory. Adsorption does not occur in the diffusive limit as is the case for many aqueous, small-molecule surfactants. Dilatational rheology reveals differences in behavior between the diblocks and triblocks, and all interfaces possess elasticities below the thermodynamic limit. Desorption dynamics show that material exchange between the interface and the neighboring fluid occurs too slowly to relax dilatational stresses. The mechanism of relaxation occurs at the interface, likely from the reorientation of adsorbed chains.
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http://dx.doi.org/10.1021/acs.langmuir.0c00477DOI Listing
July 2020

Omega-3 fatty acid exposure with a low-fat diet in patients with past hypertriglyceridemia-induced acute pancreatitis; an exploratory, randomized, open-label crossover study.

Lipids Health Dis 2020 May 30;19(1):117. Epub 2020 May 30.

AstraZeneca, Gothenburg, Sweden.

Background: Omega-3 fatty acids (OM3-FAs) are recommended with a low-fat diet for severe hypertriglyceridemia (SHTG), to reduce triglycerides and acute pancreatitis (AP) risk. A low-fat diet may reduce pancreatic lipase secretion, which is required to absorb OM3-ethyl esters (OM3-EEs), but not OM3-carboxylic acids (OM3-CAs).

Methods: In this exploratory, randomized, open-label, crossover study, 15 patients with SHTG and previous AP were instructed to take OM3-CA (2 g or 4 g) and OM3-EE 4 g once daily for 4 weeks, while adhering to a low-fat diet. On day 28 of each treatment phase, a single dose was administered in the clinic with a liquid low-fat meal, to assess 24-h plasma exposure. Geometric least-squares mean ratios were used for between-treatment comparisons of baseline (day 0)-adjusted area under the plasma concentration versus time curves (AUC) and maximum plasma concentrations (C) for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Results: Before initiating OM3-FA treatment, mean baseline fasting plasma EPA + DHA concentrations (nmol/mL) were 723 for OM3-CA 2 g, 465 for OM3-CA 4 g and 522 for OM3-EE 4 g. At week 4, mean pre-dose fasting plasma EPA + DHA concentrations increased by similar amounts (+ 735 - + 768 nmol/mL) for each treatment. During the 24-h exposure assessment (day 28), mean plasma EPA + DHA increased from pre-dose to the maximum achieved concentration by + 32.7%, + 45.8% and + 3.1% with single doses of OM3-CA 2 g, OM3-CA 4 g and OM3-EE 4 g, respectively. Baseline-adjusted AUC was 60% higher for OM3-CA 4 g than for OM3-EE 4 g and baseline-adjusted C was 94% higher (both non-significant).

Conclusions: Greater 24-h exposure of OM3-CA versus OM3-EE was observed for some parameters when administered with a low-fat meal at the clinic on day 28. However, increases in pre-dose fasting plasma EPA + DHA over the preceding 4-week dosing period were similar between treatments, leading overall to non-significant differences in baseline (day 0)-adjusted AUC and C EPA + DHA values. It is not clear why the greater 24-h exposure of OM3-CA versus OM3-EE observed with a low-fat meal did not translate into significantly higher pre-dose fasting levels of DHA + EPA with longer-term use.

Trial Registration: ClinicalTrials.gov, NCT02189252, Registered 23 June 2014.
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http://dx.doi.org/10.1186/s12944-020-01295-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260759PMC
May 2020

A novel and cost-effective orthotopic model for the study of human breast cancer in mouse mammary gland organ culture.

Biol Open 2020 05 29;9(5). Epub 2020 May 29.

Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA

Mouse mammary organ culture (MMOC) is used to evaluate the efficacy of chemopreventive agents against the development of carcinogen-induced preneoplastic lesions and is highly correlative to carcinogenesis models. Here, we developed a new MMOC model, by introducing human breast cancer cells into the mouse mammary gland. This novel model, termed human breast cancer in MMOC (BCa-MMOC), mimics orthotopic breast cancer mouse models. To develop this model, estradiol- and progesterone-sensitized female mice were injected with letrozole-sensitive and -resistant T47D breast cancer cells in the mammary glands and then euthanized. The glands were cultured with hormone-supplemented media. On day 25, the glands were fixed and processed by histopathology and immunohistochemistry to evaluate for the presence of T47D cells, growth pattern, cancer markers and estradiol responsiveness. Histopathological analyses demonstrated an identical pattern of growth between the breast cancer cells injected and Interestingly, clusters of cancer cells in the mammary gland stroma appeared similar to those observed in human breast tumors. The injected T47D cells survived and proliferated for 15 days maintaining expression of estrogen receptor alpha (ER), progesterone receptor (PR), epidermal growth factor receptor (EGFR), and aromatase. The aromatase-overexpressing T47D grown in the BCa-MMOC sufficiently metabolized estrogen, resulting in enhanced cell proliferation, induction of estrogen target genes (i.e. ER and PR-B), and showed typical changes to estrogenic milieu. In summary, here we show a novel, inexpensive model, to potentially study the effects of therapeutic agents on cancer cells grown in an orthotopic micromilieu.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/bio.051649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272353PMC
May 2020
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